CN107849124A - Anti- TAU antibody and application method - Google Patents

Anti- TAU antibody and application method Download PDF

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Publication number
CN107849124A
CN107849124A CN201680033214.6A CN201680033214A CN107849124A CN 107849124 A CN107849124 A CN 107849124A CN 201680033214 A CN201680033214 A CN 201680033214A CN 107849124 A CN107849124 A CN 107849124A
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seq
hvr
amino acid
acid sequence
antibody
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CN107849124B (en
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O·阿道夫松
G·阿亚隆
D·M·迪卡拉
I·霍策尔
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AC Immune SA
Genentech Inc
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AC Immune SA
Genentech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4709—Amyloid plaque core protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Abstract

The present invention provides anti-Tau antibody and its application method.

Description

Anti- TAU antibody and application method
The cross reference of related application
This application claims the priority for the U.S. Provisional Application No. 62/171,693 submitted on June 5th, 2015, this is interim Application is incorporated herein in entirety by reference for any purpose.
Invention field
The present invention relates to anti-Tau antibody and its application method.
Background of invention
Neurofibrillary tangles and neuropil thread (NT) are Alzheimer disease (Alzheimer ' s Disease； AD major nerve neuropathological hallmarks).NT is by having carried out the micro-pipe correlation Tau albumen structures of posttranslational modification (including phosphorylation) Into, and the aggregations of the Tau rotamers for passing through peroxophosphoric acid develops.AD and many neurodegenerative Protein taus disease, especially There are this pathology jointly with certain form of Frontotemporal dementia (FTD).Tau albumen seems to be AD and related neural degenerative The Primary Actor of forfeiture is recognized in Protein tau disease.
It is few to target the treatment method of Tau albumen, and it is main including being considered as making Tau phosphorylations improve to pathologic degree Kinases inhibitor and block peroxophosphoric acid Tau albumen cytoplasm aggregation compound.These methods are by various special Property and effect shortcoming influence.Need targeting known or speculate the pathological protein rotamer for causing neurodegenerative illness Additional therapeutic agent.
Brief summary of the invention
The present invention provides anti-Tau antibody and its application method.
In some embodiments, there is provided people Tau separated antibody is incorporated into, wherein the antibody binding is in monomer Tau, oligomerization Tau, non-phosphorylating Tau and phosphorylation Tau.In some embodiments, amino acid of the antibody binding into acquaintance Tau Epitope in 2 to 24.In some embodiments, antibody is monoclonal antibody.In some embodiments, antibody is behaved anti- Body, humanized antibody or chimeric antibody.In some embodiments, antibody is the antibody fragment with reference to people Tau.In some implementations In scheme, the people Tau includes SEQ ID NO：2 sequence.
In some embodiments, antibody includes：
A) include and be selected from SEQ ID NO：12nd, the HVR-H1 of 22,282,292 and 342 amino acid sequence；Comprising selected from SEQ ID NO：13rd, the HVR-H2 of 23,283,293 and 343 amino acid sequence；With comprising selected from SEQ ID NO：14、24、 284th, the HVR-H3 of 294 and 344 amino acid sequence；Or
B) include and be selected from SEQ ID NO：The HVR-H1 of 72 and 302 amino acid sequence；Comprising selected from SEQ ID NO：73 With the HVR-H2 of 303 amino acid sequence；With comprising selected from SEQ ID NO：The HVR-H3 of 74 and 304 amino acid sequence；
C) SEQ ID NO are included：The HVR-H1 of 42 amino acid sequence；Include SEQ ID NO：43 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 44 amino acid sequence；
D) SEQ ID NO are included：The HVR-H1 of 62 amino acid sequence；Include SEQ ID NO：63 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 64 amino acid sequence；
E) SEQ ID NO are included：The HVR-H1 of 212 amino acid sequence；Include SEQ ID NO：213 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 214 amino acid sequence；
F) SEQ ID NO are included：The HVR-H1 of 32 amino acid sequence；Include SEQ ID NO：33 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 34 amino acid sequence；Or
G) SEQ ID NO are included：The HVR-H1 of 52 amino acid sequence；Include SEQ ID NO：53 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 54 amino acid sequence.
In some embodiments, antibody includes：
A) include and be selected from SEQ ID NO：15th, the HVR-L1 of 25,285,295,345 and 468 to 556 amino acid sequence； Comprising selected from SEQ ID NO：16th, the HVR-L2 of 26,286,296 and 346 amino acid sequence；With comprising selected from SEQ ID NO： 17th, the HVR-L3 of 27,287,297 and 347 amino acid sequence；
B) include and be selected from SEQ ID NO：The HVR-L1 of 75 and 305 amino acid sequence；Comprising selected from SEQ ID NO：76 With the HVR-L2 of 306 amino acid sequence；With comprising selected from SEQ ID NO：The HVR-L3 of 77 and 307 amino acid sequence；
C) SEQ ID NO are included：The HVR-L1 of 45 amino acid sequence；Include SEQ ID NO：46 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 47 amino acid sequence；
D) SEQ ID NO are included：The HVR-L1 of 65 amino acid sequence；Include SEQ ID NO：66 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 67 amino acid sequence；
E) SEQ ID NO are included：The HVR-L1 of 215 amino acid sequence；Include SEQ ID NO：216 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 217 amino acid sequence；
F) SEQ ID NO are included：The HVR-L1 of 35 amino acid sequence；Include SEQ ID NO：36 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 37 amino acid sequence；Or
G) SEQ ID NO are included：The HVR-L1 of 55 amino acid sequence；Include SEQ ID NO：56 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 57 amino acid sequence.
In some embodiments, antibody includes：
A) include and be selected from SEQ ID NO：12nd, the HVR-H1 of 22,282,292 and 342 amino acid sequence；Comprising selected from SEQ ID NO：13rd, the HVR-H2 of 23,283,293 and 343 amino acid sequence；Comprising selected from SEQ ID NO：14、24、284、 The HVR-H3 of 294 and 344 amino acid sequence；Comprising selected from SEQ ID NO：15th, 25,285,295,345 and 468 to 556 The HVR-L1 of amino acid sequence；Comprising selected from SEQ ID NO：16th, the HVR-L2 of 26,286,296 and 346 amino acid sequence； With comprising selected from SEQ ID NO：17th, the HVR-L3 of 27,287,297 and 347 amino acid sequence；
B) include and be selected from SEQ ID NO：The HVR-H1 of 72 and 302 amino acid sequence；Comprising selected from SEQ ID NO：73 With the HVR-H2 of 303 amino acid sequence；Comprising selected from SEQ ID NO：The HVR-H3 of 74 and 304 amino acid sequence；Comprising Selected from SEQ ID NO：The HVR-L1 of 75 and 305 amino acid sequence；Comprising selected from SEQ ID NO：76 and 306 amino acid sequence The HVR-L2 of row；With comprising selected from SEQ ID NO：The HVR-L3 of 77 and 307 amino acid sequence；
C) SEQ ID NO are included：The HVR-H1 of 42 amino acid sequence；Include SEQ ID NO：43 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 44 amino acid sequence；Include SEQ ID NO：45 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 46 amino acid sequence；With include SEQ ID NO：47 amino acid sequence HVR-L3；
D) SEQ ID NO are included：The HVR-H1 of 62 amino acid sequence；Include SEQ ID NO：63 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 64 amino acid sequence；Include SEQ ID NO：65 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 66 amino acid sequence；With include SEQ ID NO：67 amino acid sequence HVR-L3；
E) SEQ ID NO are included：The HVR-H1 of 212 amino acid sequence；Include SEQ ID NO：213 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 214 amino acid sequence；Include SEQ ID NO：215 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 216 amino acid sequence；With include SEQ ID NO：217 amino acid sequence The HVR-L3 of row；
F) SEQ ID NO are included：The HVR-H1 of 32 amino acid sequence；Include SEQ ID NO：33 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 34 amino acid sequence；Include SEQ ID NO：35 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 36 amino acid sequence；With include SEQ ID NO：37 amino acid sequence HVR-L3；Or
G) SEQ ID NO are included：The HVR-H1 of 52 amino acid sequence；Include SEQ ID NO：53 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 54 amino acid sequence；Include SEQ ID NO：55 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 56 amino acid sequence；With include SEQ ID NO：57 amino acid sequence HVR-L3。
In some embodiments, antibody includes：
A) include with selected from SEQ ID NO：10th, 20,280,290 and 340 sequence has the sequence of at least 95% homogeneity The weight chain variable district (VH) of row；
B) include with selected from SEQ ID NO：11st, 21,281,291 and 341 sequence has the sequence of at least 95% homogeneity The light chain variable district (VL) of row；
C) such as the VH in (a) and such as the VL in (b)；
D) include with selected from SEQ ID NO：70th, 300 and 452 to 459 sequence has the sequence of at least 95% homogeneity Weight chain variable district (VH)；
E) include with selected from SEQ ID NO：71st, 301 and 460 to 467 sequence has the sequence of at least 95% homogeneity Light chain variable district (VL)；
F) such as the VH in (d) and such as the VL in (e)；
G) include and SEQ ID NO：40 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
H) include and SEQ ID NO：41 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
I) such as the VH in (g) and such as the VL in (h)；
J) include and SEQ ID NO：60 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
K) include and SEQ ID NO：61 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
1) such as the VH in (j) and such as the VL in (k)；
M) include and SEQ ID NO：210 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
N) include and SEQ ID NO：211 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
O) such as the VH in (m) and such as the VL in (n)；
P) include and SEQ ID NO：30 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Q) include and SEQ ID NO：31 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
R) such as the VH in (p) and such as the VL in (q)；
S) include and SEQ ID NO：50 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
T) include and SEQ ID NO：51 have the light chain variable district (VL) of at least sequence of 95% homogeneity；Or
U) such as the VH in (s) and such as the VL in (t).
In some embodiments, antibody includes：
A) include and be selected from SEQ ID NO：10th, the weight chain variable district (VH) of 20,280,290 and 340 sequence；
B) include and be selected from SEQ ID NO：11st, the light chain variable district (VL) of 21,281,291 and 341 sequence；
C) such as the VH in (a) and such as the VL in (b)；
D) include and be selected from SEQ ID NO：70th, the weight chain variable district (VH) of 300 and 452 to 459 sequence；
E) include and be selected from SEQ ID NO：71st, the light chain variable district (VL) of 301 and 460 to 467 sequence；
F) such as the VH in (d) and such as the VL in (e)；
G) SEQ ID NO are included：The weight chain variable district (VH) of 40 sequence；
H) SEQ ID NO are included：The light chain variable district (VL) of 41 sequence；
I) such as the VH in (g) and such as the VL in (h)；
J) SEQ ID NO are included：The weight chain variable district (VH) of 60 sequence；
K) SEQ ID NO are included：The light chain variable district (VL) of 61 sequence；
L) such as the VH in (j) and such as the VL in (k)；
M) SEQ ID NO are included：The weight chain variable district (VH) of 210 sequence；
N) SEQ ID NO are included：The light chain variable district (VL) of 211 sequence；
O) such as the VH in (m) and such as the VL in (n)；
P) SEQ ID NO are included：The weight chain variable district (VH) of 30 sequence；
Q) SEQ ID NO are included：The light chain variable district (VL) of 31 sequence；
R) such as the VH in (p) and such as the VL in (q)；
S) SEQ ID NO are included：The weight chain variable district (VH) of 50 sequence；
T) SEQ ID NO are included：The light chain variable district (VL) of 51 sequence；Or
U) such as the VH in (s) and such as the VL in (t).
In some embodiments, antibody includes comprising SEQ ID NO：The HVR-H1 of 342 amino acid sequence；Comprising SEQ ID NO：The HVR-H2 of 343 amino acid sequence；Include SEQ ID NO：The HVR-H3 of 344 amino acid sequence；Comprising SEQ ID NO：The HVR-L1 of 345 amino acid sequence；Include SEQ ID NO：The HVR-L2 of 346 amino acid sequence；And bag The NO of ID containing SEQ：The HVR-L3 of 347 amino acid sequence.
In some embodiments, antibody includes comprising SEQ ID NO：The weight chain variable district of 340 amino acid sequence With include SEQ ID NO：The light chain variable district of 341 amino acid sequence.
In some embodiments, antibody includes comprising SEQ ID NO：348 or SEQ ID NO：602 amino acid sequence The heavy chain of row and include SEQ ID NO：The light chain of 349 amino acid sequence.
In some embodiments, there is provided be incorporated into people Tau separated antibody, included wherein the antibody includes SEQ ID NO：348 or SEQ ID NO：The heavy chain of 602 amino acid sequence and include SEQ ID NO：349 amino acid sequence Light chain.In some embodiments, there is provided be incorporated into people Tau separated antibody, included wherein the antibody includes SEQ ID NO：The heavy chain of 348 amino acid sequence and include SEQ ID NO：The light chain of 349 amino acid sequence.In some realities Apply in scheme, there is provided people Tau separated antibody is incorporated into, wherein the antibody includes comprising SEQ ID NO：602 The heavy chain of amino acid sequence and include SEQ ID NO：The light chain of 349 amino acid sequence.In some embodiments, there is provided knot Together in people Tau separated antibody, wherein the antibody includes by SEQ ID NO：348 or SEQ ID NO：602 ammonia Base acid sequence composition heavy chain and by SEQ ID NO：The light chain of 349 amino acid sequence composition.In some embodiments, carry Separated antibody for being incorporated into people Tau, wherein the antibody includes by SEQ ID NO：348 amino acid sequence composition Heavy chain and by SEQ ID NO：The light chain of 349 amino acid sequence composition.In some embodiments, there is provided be incorporated into people Tau separated antibody, wherein the antibody includes by SEQ ID NO：602 amino acid sequence composition heavy chain and by SEQ ID NO：The light chain of 349 amino acid sequence composition.
In some embodiments, there is provided people Tau separated antibody is incorporated into, wherein the antibody binding is into acquaintance Tau amino acid/11 9 to 33,19 to 42,28 to 44,37 to 51,100 to 114,109 to 123,118 to 132,154 to 168, Epitope in 172 to 177,217 to 231 or 397 to 411.
In some embodiments, antibody includes：
A) SEQ ID NO are included：The HVR-H1 of 112 amino acid sequence；Include SEQ ID NO：113 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 114 amino acid sequence；
B) SEQ ID NO are included：The HVR-H1 of 132 amino acid sequence；Include SEQ ID NO：133 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 134 amino acid sequence；
C) SEQ ID NO are included：The HVR-H1 of 142 amino acid sequence；Include SEQ ID NO：143 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 144 amino acid sequence；
D) SEQ ID NO are included：The HVR-H1 of 152 amino acid sequence；Include SEQ ID NO：153 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 154 amino acid sequence；
E) SEQ ID NO are included：The HVR-H1 of 162 amino acid sequence；Include SEQ ID NO：163 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 164 amino acid sequence；
F) SEQ ID NO are included：The HVR-H1 of 252 amino acid sequence；Include SEQ ID NO：253 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 254 amino acid sequence；
G) SEQ ID NO are included：The HVR-H1 of 272 amino acid sequence；Include SEQ ID NO：273 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 274 amino acid sequence；
H) SEQ ID NO are included：The HVR-H1 of 102 amino acid sequence；Include SEQ ID NO：103 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 104 amino acid sequence；
I) SEQ ID NO are included：The HVR-H1 of 172 amino acid sequence；Include SEQ ID NO：173 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 174 amino acid sequence；
J) SEQ ID NO are included：The HVR-H1 of 192 amino acid sequence；Include SEQ ID NO：193 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 194 amino acid sequence；
K) SEQ ID NO are included：The HVR-H1 of 242 amino acid sequence；Include SEQ ID NO：243 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 244 amino acid sequence；
L) include and be selected from SEQ ID NO：82nd, the HVR-H1 of 312,322 and 332 amino acid sequence；Comprising selected from SEQ ID NO：83rd, the HVR-H2 of 313,323 and 333 amino acid sequence；With comprising selected from SEQ ID NO：84th, 314,324 and 334 Amino acid sequence HVR-H3；
M) SEQ ID NO are included：The HVR-H1 of 92 amino acid sequence；Include SEQ ID NO：93 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 94 amino acid sequence；
N) SEQ ID NO are included：The HVR-H1 of 122 amino acid sequence；Include SEQ ID NO：123 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 124 amino acid sequence；
O) SEQ ID NO are included：The HVR-H1 of 182 amino acid sequence；Include SEQ ID NO：183 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 184 amino acid sequence；
P) SEQ ID NO are included：The HVR-H1 of 202 amino acid sequence；Include SEQ ID NO：203 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 204 amino acid sequence；
Q) SEQ ID NO are included：The HVR-H1 of 222 amino acid sequence；Include SEQ ID NO：223 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 224 amino acid sequence；
R) SEQ ID NO are included：The HVR-H1 of 232 amino acid sequence；Include SEQ ID NO：233 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 234 amino acid sequence；Or
S) SEQ ID NO are included：The HVR-H1 of 262 amino acid sequence；Include SEQ ID NO：263 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 264 amino acid sequence.
In some embodiments, antibody includes：
A) SEQ ID NO are included：The HVR-L1 of 115 amino acid sequence；Include SEQ ID NO：116 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 117 amino acid sequence；
B) SEQ ID NO are included：The HVR-L1 of 135 amino acid sequence；Include SEQ ID NO：136 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 137 amino acid sequence；
C) SEQ ID NO are included：The HVR-L1 of 145 amino acid sequence；Include SEQ ID NO：146 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 147 amino acid sequence；
D) SEQ ID NO are included：The HVR-L1 of 155 amino acid sequence；Include SEQ ID NO：156 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 157 amino acid sequence；
E) SEQ ID NO are included：The HVR-L1 of 165 amino acid sequence；Include SEQ ID NO：166 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 167 amino acid sequence；
F) SEQ ID NO are included：The HVR-L1 of 255 amino acid sequence；Include SEQ ID NO：256 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 257 amino acid sequence；
G) SEQ ID NO are included：The HVR-L1 of 275 amino acid sequence；Include SEQ ID NO：276 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 277 amino acid sequence；
H) SEQ ID NO are included：The HVR-L1 of 105 amino acid sequence；Include SEQ ID NO：106 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 107 amino acid sequence；
I) SEQ ID NO are included：The HVR-L1 of 175 amino acid sequence；Include SEQ ID NO：176 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 177 amino acid sequence；
J) SEQ ID NO are included：The HVR-L1 of 195 amino acid sequence；Include SEQ ID NO：196 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 197 amino acid sequence；
K) SEQ ID NO are included：The HVR-L1 of 245 amino acid sequence；Include SEQ ID NO：246 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 247 amino acid sequence；
L) include and be selected from SEQ ID NO：85th, the HVR-L1 of 315,325 and 335 amino acid sequence；Comprising selected from SEQ ID NO：86th, the HVR-L2 of 316,326 and 336 amino acid sequence；With comprising selected from SEQ ID NO：87th, 317,327 and 337 Amino acid sequence HVR-L3；
M) SEQ ID NO are included：The HVR-L1 of 95 amino acid sequence；Include SEQ ID NO：96 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 97 amino acid sequence；
N) SEQ ID NO are included：The HVR-L1 of 125 amino acid sequence；Include SEQ ID NO：126 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 127 amino acid sequence；
O) SEQ ID NO are included：The HVR-L1 of 185 amino acid sequence；Include SEQ ID NO：186 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 187 amino acid sequence；
P) SEQ ID NO are included：The HVR-L1 of 205 amino acid sequence；Include SEQ ID NO：206 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 207 amino acid sequence；
Q) SEQ ID NO are included：The HVR-L1 of 225 amino acid sequence；Include SEQ ID NO：226 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 227 amino acid sequence；
R) SEQ ID NO are included：The HVR-L1 of 235 amino acid sequence；Include SEQ ID NO：236 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 237 amino acid sequence；Or
S) SEQ ID NO are included：The HVR-L1 of 265 amino acid sequence；Include SEQ ID NO：266 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 267 amino acid sequence.
In some embodiments, antibody includes：
A) SEQ ID NO are included：The HVR-H1 of 112 amino acid sequence；Include SEQ ID NO：113 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 114 amino acid sequence；Include SEQ ID NO：115 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 116 amino acid sequence；With include SEQ ID NO：117 amino acid sequence The HVR-L3 of row；
B) SEQ ID NO are included：The HVR-H1 of 132 amino acid sequence；Include SEQ ID NO：133 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 134 amino acid sequence；Include SEQ ID NO：135 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 136 amino acid sequence；With include SEQ ID NO：137 amino acid sequence The HVR-L3 of row；
C) SEQ ID NO are included：The HVR-H1 of 142 amino acid sequence；Include SEQ ID NO：143 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 144 amino acid sequence；Include SEQ ID NO：145 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 146 amino acid sequence；With include SEQ ID NO：147 amino acid sequence The HVR-L3 of row；
D) SEQ ID NO are included：The HVR-H1 of 152 amino acid sequence；Include SEQ ID NO：153 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 154 amino acid sequence；Include SEQ ID NO：155 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 156 amino acid sequence；With include SEQ ID NO：157 amino acid sequence The HVR-L3 of row；
E) SEQ ID NO are included：The HVR-H1 of 162 amino acid sequence；Include SEQ ID NO：163 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 164 amino acid sequence；Include SEQ ID NO：165 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 166 amino acid sequence；With include SEQ ID NO：167 amino acid sequence The HVR-L3 of row；
F) SEQ ID NO are included：The HVR-H1 of 252 amino acid sequence；Include SEQ ID NO：253 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 254 amino acid sequence；Include SEQ ID NO：255 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 256 amino acid sequence；With include SEQ ID NO：257 amino acid sequence The HVR-L3 of row；Or
G) SEQ ID NO are included：The HVR-H1 of 272 amino acid sequence；Include SEQ ID NO：273 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 274 amino acid sequence；Include SEQ ID NO：275 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 276 amino acid sequence；With include SEQ ID NO：277 amino acid sequence The HVR-L3 of row；
H) SEQ ID NO are included：The HVR-H1 of 102 amino acid sequence；Include SEQ ID NO：103 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 104 amino acid sequence；Include SEQ ID NO：105 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 106 amino acid sequence；With include SEQ ID NO：107 amino acid sequence The HVR-L3 of row；
I) SEQ ID NO are included：The HVR-H1 of 172 amino acid sequence；Include SEQ ID NO：173 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 174 amino acid sequence；Include SEQ ID NO：175 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 176 amino acid sequence；With include SEQ ID NO：177 amino acid sequence The HVR-L3 of row；
J) SEQ ID NO are included：The HVR-H1 of 192 amino acid sequence；Include SEQ ID NO：193 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 194 amino acid sequence；Include SEQ ID NO：195 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 196 amino acid sequence；With include SEQ ID NO：197 amino acid sequence The HVR-L3 of row；Or
K) SEQ ID NO are included：The HVR-H1 of 242 amino acid sequence；Include SEQ ID NO：243 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 244 amino acid sequence；Include SEQ ID NO：245 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 246 amino acid sequence；With include SEQ ID NO：247 amino acid sequence The HVR-L3 of row；
L) include and be selected from SEQ ID NO：82nd, the HVR-H1 of 312,322 and 332 amino acid sequence；Comprising selected from SEQ ID NO：83rd, the HVR-H2 of 313,323 and 333 amino acid sequence；Comprising selected from SEQ ID NO：84th, 314,324 and 334 The HVR-H3 of amino acid sequence；Comprising selected from SEQ ID NO：85th, the HVR-L1 of 315,325 and 335 amino acid sequence；Comprising Selected from SEQ ID NO：86th, the HVR-L2 of 316,326 and 336 amino acid sequence；With comprising selected from SEQ ID NO：87、317、 The HVR-L3 of 327 and 337 amino acid sequence；
M) SEQ ID NO are included：The HVR-H1 of 92 amino acid sequence；Include SEQ ID NO：93 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 94 amino acid sequence；Include SEQ ID NO：95 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 96 amino acid sequence；With include SEQ ID NO：97 amino acid sequence HVR-L3；
N) SEQ ID NO are included：The HVR-H1 of 122 amino acid sequence；Include SEQ ID NO：123 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 124 amino acid sequence；Include SEQ ID NO：125 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 126 amino acid sequence；With include SEQ ID NO：127 amino acid sequence The HVR-L3 of row；
O) SEQ ID NO are included：The HVR-H1 of 182 amino acid sequence；Include SEQ ID NO：183 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 184 amino acid sequence；Include SEQ ID NO：185 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 186 amino acid sequence；With include SEQ ID NO：187 amino acid sequence The HVR-L3 of row；
P) SEQ ID NO are included：The HVR-H1 of 202 amino acid sequence；Include SEQ ID NO：203 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 204 amino acid sequence；Include SEQ ID NO：205 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 206 amino acid sequence；With include SEQ ID NO：207 amino acid sequence The HVR-L3 of row；
Q) SEQ ID NO are included：The HVR-H1 of 222 amino acid sequence；Include SEQ ID NO：223 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 224 amino acid sequence；Include SEQ ID NO：225 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 226 amino acid sequence；With include SEQ ID NO：227 amino acid sequence The HVR-L3 of row；
R) SEQ ID NO are included：The HVR-H1 of 232 amino acid sequence；Include SEQ ID NO：233 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 234 amino acid sequence；Include SEQ ID NO：235 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 236 amino acid sequence；With include SEQ ID NO：237 amino acid sequence The HVR-L3 of row；Or
S) SEQ ID NO are included：The HVR-H1 of 262 amino acid sequence；Include SEQ ID NO：263 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 264 amino acid sequence；Include SEQ ID NO：265 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 266 amino acid sequence；With include SEQ ID NO：267 amino acid sequence The HVR-L3 of row.
In some embodiments, antibody includes：
A) include and SEQ ID NO：110 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
B) include and SEQ ID NO：111 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
C) such as the VH in (a) and such as the VL in (b)；
D) include and SEQ ID NO：130 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
E) include and SEQ ID NO：131 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
F) such as the VH in (d) and such as the VL in (e)；
G) include and SEQ ID NO：140 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
H) include and SEQ ID NO：141 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
I) such as the VH in (g) and such as the VL in (h)；
J) include and SEQ ID NO：150 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
K) include and SEQ ID NO：151 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
L) such as the VH in (j) and such as the VL in (k)；
M) include and SEQ ID NO：160 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
N) include and SEQ ID NO：161 have the light chain variable district (VL) of at least sequence of 95% homogeneity；Or
O) such as the VH in (m) and such as the VL in (n)；
P) include and SEQ ID NO：250 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Q) include and SEQ ID NO：251 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
R) such as the VH in (p) and such as the VL in (q)；
S) include and SEQ ID NO：270 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
T) include and SEQ ID NO：271 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
U) such as the VH in (s) and such as the VL in (t)；
V) include and SEQ ID NO：100 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
W) include and SEQ ID NO：101 have the light chain variable district (VL) of at least sequence of 95% homogeneity；Or
X) such as the VH in (v) and such as the VL in (w)；
Y) include and SEQ ID NO：170 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Z) include and SEQ ID NO：171 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
Aa) such as the VH in (y) and such as the VL in (z)；
Bb) include and SEQ ID NO：190 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Cc) include and SEQ ID NO：191 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
Dd) such as the VH in (bb) and such as the VL in (cc)；
Ee) include and SEQ ID NO：240 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Ff) include and SEQ ID NO：241 have the light chain variable district (VL) of at least sequence of 95% homogeneity；Or
Gg) such as the VH in (ee) and such as the VL in (ff)；
Hh) include with selected from SEQ ID NO：80th, 310,320,330 and 446 to 451 sequence is same with least 95% The weight chain variable district (VH) of the sequence of property；
Ii) include with selected from SEQ ID NO：81st, 311,321,331 and 442 to 445 sequence is same with least 95% The light chain variable district (VL) of the sequence of property；
Jj) such as the VH in (hh) and such as the VL in (ii)；
Kk) include and SEQ ID NO：90 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Ll) include and SEQ ID NO：91 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
Mm) such as the VH in (kk) and such as the VL in (ll)；
Nn) include and SEQ ID NO：120 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Oo) include and SEQ ID NO：121 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
Pp) such as the VH in (nn) and such as the VL in (oo)；
Qq) include and SEQ ID NO：180 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Rr) include and SEQ ID NO：181 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
Ss) such as the VH in (qq) and such as the VL in (rr)；
Tt) include and SEQ ID NO：200 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Uu) include and SEQ ID NO：201 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
Vv) such as the VH in (tt) and such as the VL in (uu)；
Ww) include and SEQ ID NO：220 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Xx) include and SEQ ID NO：221 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
Yy) such as the VH in (ww) and such as the VL in (xx)；
Zz) include and SEQ ID NO：230 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Aaa) include and SEQ ID NO：231 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
Bbb) such as the VH in (zz) and such as the VL in (aaa)；
Ccc) include and SEQ ID NO：260 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
Ddd) include and SEQ ID NO：261 have the light chain variable district (VL) of at least sequence of 95% homogeneity；Or
Eee) such as the VH in (ccc) and such as the VL in (ddd).
In some embodiments, antibody includes：
A) SEQ ID NO are included：The weight chain variable district (VH) of 110 sequence；
B) SEQ ID NO are included：The light chain variable district (VL) of 111 sequence；
C) such as the VH in (a) and such as the VL in (b)；
D) SEQ ID NO are included：The weight chain variable district (VH) of 130 sequence；
E) SEQ ID NO are included：The light chain variable district (VL) of 131 sequence；
F) such as the VH in (d) and such as the VL in (e)；
G) SEQ ID NO are included：The weight chain variable district (VH) of 140 sequence；
H) SEQ ID NO are included：The light chain variable district (VL) of 141 sequence；
I) such as the VH in (g) and such as the VL in (h)；
J) SEQ ID NO are included：The weight chain variable district (VH) of 150 sequence；
K) SEQ ID NO are included：The light chain variable district (VL) of 151 sequence；
L) such as the VH in (j) and such as the VL in (k)；
M) SEQ ID NO are included：The weight chain variable district (VH) of 160 sequence；
N) SEQ ID NO are included：The light chain variable district (VL) of 161 sequence；Or
O) such as the VH in (m) and such as the VL in (n)；
P) SEQ ID NO are included：The weight chain variable district (VH) of 250 sequence；
Q) SEQ ID NO are included：The light chain variable district (VL) of 251 sequence；
R) such as the VH in (p) and such as the VL in (q)；
S) SEQ ID NO are included：The weight chain variable district (VH) of 270 sequence；
T) SEQ ID NO are included：The light chain variable district (VL) of 271 sequence；Or
U) such as the VH in (s) and such as the VL in (t)
V) SEQ ID NO are included：The weight chain variable district (VH) of 100 sequence；
W) SEQ ID NO are included：The light chain variable district (VL) of 101 sequence；Or
X) such as the VH in (v) and such as the VL in (w)；
Y) SEQ ID NO are included：The weight chain variable district (VH) of 170 sequence；
Z) SEQ ID NO are included：The light chain variable district (VL) of 171 sequence；
Aa) such as the VH in (y) and such as the VL in (z)；
Bb SEQ ID NO) are included：The weight chain variable district (VH) of 190 sequence；
Cc SEQ ID NO) are included：The light chain variable district (VL) of 191 sequence；
Dd) such as the VH in (bb) and such as the VL in (cc)；
Ee SEQ ID NO) are included：The weight chain variable district (VH) of 240 sequence；
Ff SEQ ID NO) are included：The light chain variable district (VL) of 241 sequence；
Gg) such as the VH in (ee) and such as the VL in (ff)；
Hh) include and be selected from SEQ ID NO：80th, the weight chain variable district (VH) of 310,320,330 and 446 to 451 sequence；
Ii) include and be selected from SEQ ID NO：81st, the light chain variable district (VL) of 311,321,331 and 442 to 445 sequence；
Jj) such as the VH in (hh) and such as the VL in (ii)；
Kk SEQ ID NO) are included：The weight chain variable district (VH) of 90 sequence；
Ll SEQ ID NO) are included：The light chain variable district (VL) of 91 sequence；
Mm) such as the VH in (kk) and such as the VL in (ll)；
Nn SEQ ID NO) are included：The weight chain variable district (VH) of 120 sequence；
Oo SEQ ID NO) are included：The light chain variable district (VL) of 121 sequence；
Pp) such as the VH in (nn) and such as the VL in (oo)；
Qq SEQ ID NO) are included：The weight chain variable district (VH) of 180 sequence；
Rr SEQ ID NO) are included：The light chain variable district (VL) of 181 sequence；
Ss) such as the VH in (qq) and such as the VL in (rr)；
Tt SEQ ID NO) are included：The weight chain variable district (VH) of 200 sequence；
Uu SEQ ID NO) are included：The light chain variable district (VL) of 201 sequence；
Vv) such as the VH in (tt) and such as the VL in (uu)；
Ww SEQ ID NO) are included：The weight chain variable district (VH) of 220 sequence；
Xx SEQ ID NO) are included：The light chain variable district (VL) of 221 sequence；
Yy) such as the VH in (ww) and such as the VL in (xx)；
Zz SEQ ID NO) are included：The weight chain variable district (VH) of 230 sequence；
Aaa SEQ ID NO) are included：The light chain variable district (VL) of 231 sequence；
Bbb) such as the VH in (zz) and such as the VL in (aaa)；
Ccc SEQ ID NO) are included：The weight chain variable district (VH) of 260 sequence；
Ddd SEQ ID NO) are included：The light chain variable district (VL) of 261 sequence；Or
Eee) such as the VH in (ccc) and such as the VL in (ddd).
In any one embodiment described herein, antibody can be IgG1 or IgG4 antibody.Described herein In any one embodiment, antibody can be IgG4 antibody.In some such embodiments, antibody include M252Y, S254T and T256E is mutated.In any one embodiment described herein, antibody can include S228P and be mutated.At described herein In one embodiment, antibody can include S228P, M252Y, S254T and T256E and be mutated.In any one reality described herein Apply in scheme, antibody can be the IgG4 antibody for including S228P, M252Y, S254T and T256E mutation.In some embodiments, Antibody is antibody fragment.In any one embodiment described herein, antibody can be comprising S228P, M252Y, S254T and T256E is mutated and lacks the IgG4 antibody of the C-terminal lysine (des-K) of heavy chain constant region.The C-terminal lysine of heavy chain constant region can Such as removed during antibody purification, or by carrying out recombined engineering transformation to the nucleic acid of encoding said antibody not encode C-terminal lysine removes.
In some embodiments, there is provided a kind of combination people Tau separated antibody, wherein the antibody with less than 100nM, the K less than 75nM or less than 50nMDWith reference to every in monomer Tau, phosphorylation Tau, non-phosphorylating Tau and oligomerization Tau One.In some embodiments, antibody binding machin Tau (SEQ ID NO：4).
In some embodiments, there is provided a kind of separated nucleic acid, wherein the separated nucleic acid encodes this paper institutes The antibody of description.In some embodiments, there is provided a kind of host cell, retouched herein wherein the host cell includes coding The separated nucleic acid for the antibody stated.In some embodiments, there is provided a kind of method for producing antibody, it, which is included in, is suitable for Produce and cultivate host cell under conditions of the antibody.
In some embodiments, there is provided a kind of immunoconjugates, wherein the immunoconjugates are comprising described herein Separated antibody and therapeutic agent.In some embodiments, there is provided a kind of labeled antibody, it includes described herein Antibody and detectable mark.
In some embodiments, there is provided a kind of pharmaceutical composition, its include separated antibody described herein and Pharmaceutically acceptable carrier.
In some embodiments, there is provided a kind of method for treating Tau protein related diseases, it is included to Tau eggs The individual of white relevant disease applies antibody described herein or includes the pharmaceutical composition of antibody described herein.At some In embodiment, Tau protein related diseases are Protein tau disease.In some embodiments, Protein tau disease is neurodegenerative Protein tau disease.In some embodiments, Protein tau disease is selected from Alzheimer disease, amyotrophic lateral sclerosis, pa gold Gloomy disease (Parkinson ' s disease), gram refined Er Shi sick (Creutzfeldt-Jacob disease), dementia pugilistica, Tang Cotard (Down ' s Syndrome), lattice are applied and thank to San Shi diseases (Gerstmann--Scheinker Disease), inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/ Guam parkinsonism-dementia complex (parkinsonism-dementia complex of Guam), with neural fibril Tie up the non-Guam type motor neuron disease tangled, argyrophilic grain dementia, corticobasal degeneration, the diffusivity with calcification Neurofibrillary tangles, Frontotemporal dementia, Frontotemporal dementia, the Halle of chain companion's parkinson's syndrome in No. 17 chromosome are irrigated Deng-Shi Paci diseases (Hallevorden-Spatz disease), multiple system atrophy, c-type Niemann-Pick disease (Niemann-Pick disease type C), globus pallidus-ponto-nigral degeneration disease, Pick disease (Pick ' s disease), Glial cells hyperplasia disease under progressive cortex, paralysis on progressive core, subacute sclerosing panencephalitis, only entanglement type is dull-witted, brain Parkinson's syndrome and myotonia atrophica after inflammation.In some embodiments, Protein tau disease for Alzheimer disease or Benumbed on progressive core.
In some embodiments, there is provided one kind keeps in individual or improves cognition and memory ability or slow down the loss of memory Method, it includes using antibody described herein or includes the pharmaceutical composition of antibody described herein.
In some embodiments, there is provided one kind reduces Tau albumen, non-phosphorylating Tau albumen, phosphorylation Tau in individual The horizontal method of albumen or peroxophosphoric acid Tau albumen, it is included using antibody described herein or comprising described herein Antibody pharmaceutical composition.
In some embodiments, there is provided separated antibody described herein is for use as medicament.In some embodiment party In case, there is provided separated antibody described herein is sick for treating Protein tau in individual.In some embodiments In, Protein tau disease is neurodegenerative Protein tau disease.In some embodiments, Protein tau disease selected from Alzheimer disease, Amyotrophic lateral sclerosis, Parkinson's, gram refined Er Shi diseases, dementia pugilistica, Down syndrome, lattice are applied and thank to San Shi diseases, forgive Body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam Parkinson are comprehensive Simulator sickness-dementia complex, with non-Guam type motor neuron disease of neurofibrillary tangles, argyrophilic grain dementia, cortex base Bottom core degeneration disease, with the Diffuse neurofibrillary entanglement of calcification, Frontotemporal dementia, chain companion's pa gold in No. 17 chromosome It is the Frontotemporal dementia of gloomy syndrome, Hallervorden Spatz disease, multiple system atrophy, c-type Niemann-Pick disease, pale It is glial cells hyperplasia disease under ball-ponto-nigral degeneration disease, Pick disease, progressive cortex, paralysis on progressive core, subacute hard The property changed panencephalitis, only entanglement type dementia, postencephalitic parkinsonism and myotonia atrophica.In some embodiments In, Protein tau disease is to be benumbed on Alzheimer disease or progressive core.
In some embodiments, there is provided separated antibody described herein is for the holding in individual or improves Cognition and memory ability slows down the loss of memory.In some embodiments, there is provided separated antibody described herein with In the level for reducing Tau albumen in individual, phosphorylated Tau protein, non-phosphorylating Tau albumen or peroxophosphoric acid Tau albumen.
In some embodiments, there is provided the purposes of antibody described herein, it, which is used to manufacture, is used to control in individual Treat the medicament of Tau protein related diseases.In some embodiments, Tau protein related diseases are Protein tau disease.In some realities Apply in scheme, Protein tau disease is neurodegenerative Protein tau disease.In some embodiments, Protein tau disease is selected from A Erci The silent disease in sea, amyotrophic lateral sclerosis, Parkinson's, gram refined Er Shi diseases, dementia pugilistica, Down syndrome, lattice are applied and thank to San Shi Disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam pa Gloomy syndrome-the dementia complex of gold, with non-Guam type motor neuron disease of neurofibrillary tangles, argyrophilic grain dementia, Corticobasal degeneration, with the Diffuse neurofibrillary entanglement of calcification, Frontotemporal dementia, chain in No. 17 chromosome With the Frontotemporal dementia of parkinson's syndrome, Hallervorden Spatz disease, multiple system atrophy, c-type Niemann-Pick disease, It is glial cells hyperplasia disease under globus pallidus-ponto-nigral degeneration disease, Pick disease, progressive cortex, paralysis on progressive core, sub- anxious Property sclerosing panencephalitis, only entanglement type is dull-witted, postencephalitic parkinsonism and myotonia atrophica.In some embodiment party In case, Protein tau disease is to be benumbed on Alzheimer disease or progressive core.
In some embodiments, there is provided the purposes of antibody described herein, it, which is used to manufacture, is used to protect in individual Hold or improve cognition and memory ability or slow down the medicament of the loss of memory.
In some embodiments, there is provided one kind detection neurofibrillary tangles, neuropil thread or dystrophic Neuritic method, it includes making sample contact with antibody described herein.In some embodiments, sample is brain sample Product, celiolymph sample or blood sample.
In any one embodiment described herein, method or purposes can be included and combined with least one additional therapy Using antibody described herein.The non-limiting examples of additional therapy include neurologic agent, corticosteroid, antibiotic, anti- Viral agent and other therapeutic agents.Such other therapeutic agents include but is not limited to other anti-Tau antibody, for amyloid-β Antibody, for the antibody of beta-secretase ferment 1 (" BACE1 ") and the inhibitor of beta-secretase ferment 1.
Brief description
Antibody binding in peroxophosphoric acid Tau (pTau) combination and is incorporated into non-phosphorylating by Figure 1A-F. using ELISA Tau combination compares.As a result represented with optical density (OD) (O.D.).
Fig. 2A-E. assess antibody and oligomerization Tau combination using few Tau and single Tau capturing ELISAs.As a result it is close with optics (O.D.) is spent to represent.
Fig. 3 using Western blotting (WB) determine, the three kinds of general Tau antibody displays tested its be incorporated into from A Er Soluble T au in the brain lysate of Ci Haimo diseases (AD) and matching control donor.Make from AD and compare brain lysate Protein extract and six kinds of recombined human Tau isotypes in SDS-PAGE and with three kinds of general Tau antibody (37D3-H9,94B2- C1 and 125B11-H3) run on the film of blotting.Swimming lane with AD samples is labeled as AD18, AD24 and AD27, and has The swimming lane for having control sample is labeled as C25 and C21.The swimming lane run with six kinds of recombined human Tau isotypes is labeled as hTau sequences Ladder.
Fig. 4 A-C. use Tau capturing ELISAs, general Tau antibody displays its be incorporated into the brain from AD and matching control donor Soluble T au in lysate.Show three kinds of general Tau antibody 37D3-H9,94B2-C1 and 125B11-H3 data.As a result With optical density (OD) (O.D.), average value ± SD, N=2 expression.
Fig. 5 show 37D3-H9 (left figure) and (right figure) is incorporated into and Biacore chip lists in the form of IgG in the form of Fab The sensing figure of people's Tau monomers of face covalent coupling.1: 1 binding model is applied, and is shown as overlapping.X-axis instruction time (unit =the second).Y-axis instruction resonance units (RU).
Fig. 6 displaying hu37D3-H9.v5 samples t=0 (left figure) and t=2 weeks (right figure) are incorporated into 3.1,6.3,12.5, 25th, the overlapping sensing figure of 25,50 and 100nM people's Tau monomers.1: 1 binding model is applied, and is also illustrated in this figure.X-axis Instruction time (unit=second).Y-axis instruction resonance units (RU).
Fig. 7 .hu37D3-H9.v5 and hu37D3-H9.v5 N28D are respectively in connection with monomer Tau, (left figure shows hu37D3- H9.v5 and middle graph shows hu37D3-H9.v5 N28D) and with 1: 1 ratio mix (right figure) combination.X-axis instruction time is (single Position=the second).Y-axis instruction resonance units (RU).
Fig. 8 A-D. screen affinity, stability index and the sequence of 90 kinds of 37D3-H9 variants for potential improved stability Row.For the sake of clarity, start in each experiment, it is middle and at the end of the use that runs stress control antibodies (hu37D3- H9.v5 hIgG1) value that is obtained is illustrated in two parts of table.
The position of Fig. 9 displaying light chain residues 28 to 33 (NGNTYF motifs) and the 37D3- of the relative position of residue 28 and 33 The structural model in H9 Fv areas.It should be noted that the residue 33 that Leu is sported in hu37D3.v28.A4 is not adjacent to unstable Asn-28 Residue.Hydrogen bond between dotted line displaying residue A sn-28 and Tyr-32.Use MOE software kits (Chemical Computing Group figure) is produced.
Figure 10 is illustrated in single 10mg/kg intravenously or after intraperitoneal injection, and anti-Tau antibody 37D3-H9 is in mouse Pharmacokinetics.
Figure 11 be illustrated in after the single dose IV fast injections with 1mg/kg hu37D3.v28.A4hIgG4-S228P and Pharmacokinetics of the hu37D3.v28.A4 hIgG4-S228P.YTE in machin.
The combination of some anti-Tau antibody of Figure 12 A-C. and Tau fragments.(A) some anti-Tau antibody and Tau fragments 1- are shown 15th, 10-24,19-33,28-42,37-51 and 46-60 combination.(B) antibody 37D3-H9 mIgG2a and Tau fragments 10-44, 10-24,2-24,2-34 and total length Tau combination.(C) antibody hu37D3-H9.v5 hIgG1 and Tau fragments 10-44,10-24, 2-24,2-34 and total length Tau combination.
Figure 13 A-B. are in neuron-microglia cell coculture, influence of the effector function to Tau toxicity.(A) MAP2 fragmentation percentages in the coculture contacted with various antibody and oligomerization Tau.(B) with various antibody and oligomerization The neuron (top graph) of Tau contacts and the image of neuron-microglia cell coculture (bottom diagram).
Figure 14 are in the sea for the mouse for applying anti-tau 37D3-H9 WT IgG2a or anti-tau 37D3-H9 DANG IgG2 The pTau212/214 of Malaysia and China is horizontal.
Figure 15 people and the comparison of machin Tau sequences.Epitope of the indicator to antibody 37D3-H9.
Figure 16 is illustrated in single 10mg/kg intravenously or after intraperitoneal injection, and anti-Tau antibody 94B2-C1 is in mouse Pharmacokinetics.
Figure 17 is illustrated in single 10mg/kg intravenously or after intraperitoneal injection, and anti-Tau antibody 125B11-H3 is in mouse Pharmacokinetics.
Figure 18 displayings hu37D3-H9.v1, hu37D3-H9.v39, hu37D3-H9.v40 and hu37D3-H9.v41 κ 1 are light The comparison of chain variable region.
Figure 19 A-B be illustrated in 50mg/kg singles IV inject specify antibody after, the plasma antibody concentration (A) in machin With CSF antibody concentrations (B).
Figure 20 be illustrated in 50mg/kg singles IV inject specify antibody after, the total Tau concentration of blood plasma and blood plasma in machin Antibody concentration.
Figure 21 A-D be illustrated in 50mg/kg singles IV injection hu37D3.v28.A4 hIgG4-S228P (A) and Hu37D3.v28.A4 hIgG4-S228P.YTE (B) afterwards 2 days and 10 days when, the antibody concentration in each area of machin brain；In brain Average antibody concentration (C)；Brain：Plasma antibody concentration % (D).
Figure 22 A-B displayings are with logarithm (A) and linear (B) scale, with the specified antibody of 50mg/kg singles IV injections Antibody concentration during rear Each point in time in machin brain.
When Figure 23 A-E are illustrated in the Each point in time after specified antibody is injected with 50mg/kg singles IV, in the sea of machin Antibody concentration in horse (A), cerebellum (B), volume cortex (C), CSF (D) and blood plasma (E).
Figure 24 A-B are illustrated in so that after the specified antibody of 50mg/kg singles IV injections, what is changed over time in machin is averaged And indivedual total Tau concentration of (B) blood plasma (A).
Embodiment
I. define
For the purposes herein, " acceptor people framework " is comprising from human immunoglobulin(HIg) structure as defined below Frame or people share the framework of light-chain variable domain (VL) framework of framework or the amino acid sequence of heavy chain variable domain (VH) framework." come Coming from " human immunoglobulin(HIg) framework or people share the acceptor people framework of framework can include human immunoglobulin(HIg) framework or people share The same amino acid sequence of framework, or its can contain amino acid sequence change.In some embodiments, the number of amino acid change Mesh be 10 or less than 10,9 or less than 9,8 or less than 8,7 or less than 7,6 or less than 6,5 or 5 It is individual it is following, 4 or less than 4,3 or less than 3 or 2 or less than 2.In some embodiments, VL acceptors people structure The sequence of frame shares frame sequence with VL human immunoglobulin(HIg)s frame sequence or people has homogeneity.
" affinity " refers between the single binding site of molecule (such as antibody) collocation thing (such as antigen) in connection Noncovalent interaction summation intensity.Unless otherwise instructed, otherwise as used herein, " binding affinity " refers to reflect With reference to the intrinsic binding affinity to 1: 1 interaction between (such as antibody and antigen) member.Molecule X arranges in pairs or groups thing Y to it Affinity typically can be by dissociation constant (KD) represent.Can be (including described herein by common method as known in the art Those methods) measure affinity.Certain illustrative and exemplary embodiment for measuring binding affinity are described in Hereinafter.
" affinity maturation " antibody refers to without one or more change compared in one or more hypervariable regions (HVR) The parental antibody of change, has the antibody of such change, and these changes make antibody improve the affinity of antigen.
Term " anti-Tau antibody " and " antibody for being incorporated into Tau " are referred to enough affinity combination Tau antibody, So that the antibody is suitable for targetting Tau diagnosticum and/or therapeutic agent.In some embodiments, anti-Tau antibody nothing to do with The protein bound degree of non-Tau be less than the antibody and Tau combination about 10%, such as example, by radiommunoassay (RIA) it is measured.In certain embodiments, it is incorporated into dissociation constant (the K of Tau antibodyD)≤1μM、≤100nM、≤ 10nM ,≤1nM ,≤0.1nM ,≤0.01nM or≤0.001nM (such as 10-8M or 10-8Below M, such as 10-8M to 10-13M, example Such as 10-9M to 10-13M).In certain embodiments, anti-Tau antibody bindings are in Tau epitope, and the epitope is from not jljl Has conservative in the Tau of kind.Unless other special instructions, otherwise as used herein, term " anti-Tau antibody " and " Tau is incorporated into Antibody " refer to antibody with reference to monomer Tau, oligomerization Tau and/or phosphorylation Tau.In some such embodiments, anti-Tau Antibody is such as incorporated into monomer Tau, oligomerization Tau, non-phosphorus with similar affinity with the affinity differed each other no more than 50 times It is acidified Tau and phosphorylation Tau.In some embodiments, with reference to monomer Tau, oligomerization Tau, non-phosphorylating Tau and phosphorylation Tau antibody is referred to as " general Tau antibody ".
Term " antibody " is used with largest sense and covers various antibody structures herein, including but not limited to single Clonal antibody, polyclonal antibody, multi-specificity antibody (such as bispecific antibody) and antibody fragment, as long as it shows required resist Former binding activity.
" antibody fragment " refers to the molecule in addition to complete antibody, and it is included in complete antibody with reference to the complete antibody institute With reference to antigen part.The example of antibody fragment includes but is not limited to Fv, Fab, Fab ', Fab '-SH, F (ab ')2；Double-strand Antibody；Line antibody；Single-chain antibody molecules (such as scFv)；With the multi-specificity antibody formed by antibody fragment.
Refer to reference antibody " antibody for being incorporated into same epitope " in competition assay, block reference antibody and its antigen Antibody of the combination up to 50% or more than 50%, and on the contrary, in competition assay, reference antibody blocks the antibody anti-with it Former combination is up to 50% or more than 50%.Provided herein is a kind of exemplary competition assay.
Term " chimeric " antibody refers to that a part for heavy chain and/or light chain derives from particular source or species, and described heavy The remainder of chain and/or light chain is from separate sources or the antibody of species.
" classification " of antibody refers to the type of constant domain or constant region possessed by its heavy chain.In the presence of five kinds of primary categories Antibody：IgA, IgD, IgE, IgG and IgM, and some persons in these classifications can be further separated into subclass (homotype), such as IgG1、IgG2、IgG3、IgG4、IgA1And IgA2.Corresponding to different classes of immunoglobulin heavy-chain constant domains be referred to as α, δ, ε, γ and μ.
Term " cytotoxic agent " as used herein refer to suppress or hinder cell function and/or cause cell death or The material of destruction.Cytotoxic agent includes but is not limited to radio isotope (such as At211、I131、I125、Y90、Re186、 Re188、Sm153、Bi212、P32、Pb212With Lu radio isotope)；Chemotherapeutant or medicine (such as methotrexate (methotrexate), adriamycin (adriamicin), vinca alkaloids (vincristine (vincristine), vincaleukoblastinum (vinblastine), Etoposide (etoposide)), Doxorubicin (doxorubicin), melphalan (melphalan), silk Rimocidin C (mitomycinC), Chlorambucil (chlorambucil), daunomycin (daunorubicin) or other insertions Agent)；Growth inhibitor；Enzyme and its fragment, such as nucleolytic enzyme；Antibiotic；Toxin, such as small molecule toxins or bacterium, fungi, plant The enzyme activity toxin of thing or animal origin, including its fragment and/or variant；And various antitumor or anticancer as disclosed below Agent.
" effector function " refers to those bioactivity in the Fc areas for being attributable to antibody, and it changes with antibody morphism.Antibody The example of effector function includes：Clq is combined and complement-dependent cytotoxicity (CDC)；Fc acceptors combine；Antibody dependent cellular The cytotoxicity (ADCC) of mediation；Phagocytosis；The downward of cell surface receptor (such as B-cell receptor)；Activated with B cell.
" effective dose " of medicament (such as pharmaceutical preparation) refers to effectively reach institute with necessary dosage and lasting necessary time section The amount of result need to be treated or prevented.
This paper term " Fc areas " is used to define at least one of heavy chain immunoglobulin C-terminal area containing constant region. The term includes native sequence Fc areas and variant Fc areas.In some embodiments, human IgG heavy chain Fc areas from Cys226 or from Pro230 extends to the c-terminus of heavy chain.However, the C-terminal lysine (Lys447) in Fc areas may be present or absent.Unless this Literary explanation in addition, otherwise the numbering of amino acid residue is according to EU numbering systems, also referred to as EU indexes, such as in Fc areas or constant region Kabat et al., Sequences of Proteins of Immunological Interest, the 5th edition Public Health Department (Public Health Service), NIH (National Institutes of Health), Described in Bethesda, MD, 1991.
" framework " or " FR " refers to the variable domain residue in addition to hypervariable region (HVR) residue.The FR of variable domain is typically by four Individual FR domains composition：FRI, FR2, FR3 and FR4.Therefore, HVR and FR sequences are typically appeared in VH (or VL) with following sequence： FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4。
Term " full length antibody ", " complete antibody " and " whole antibody " is used interchangeably herein and refers to structure substantially Similar to primary antibody structure or with containing Fc areas as herein defined heavy chain antibody.
Term " host cell ", " host cell strain " and " host cell cultures " is used interchangeably and refers to have been introduced into outside The cell of source nucleic acid, include the offspring of such cell.Host cell includes " transformant " and " transformed cells ", and it includes primary and turned Change cell and by its derivative offspring's (not considering passage number).The nucleic acid content of offspring may incomplete phase with parental cell Together, but may contain mutation.Include having with screening or selecting identical function or biology for original transformation cell herein The Mutant progeny of activity.
" human antibody " be amino acid sequence correspond to produced by people or people's cell or from using human antibody pedigree or its The antibody of the amino acid sequence of the antibody of the non-people source of other people antibody coding sequences.Human antibody this define given row remove comprising The humanized antibody of non-human antigen-binding residues.
Term " variable region " or " variable domain " refer to heavy chain of antibody or the light chain domain for participating in antibody and antigen binding.It is primary anti- The heavy chain of body typically has similar structure with the variable domain of light chain (being respectively VH and VL), wherein each domain includes four Conservative framework region (FR) and three hypervariable regions (HVR).(see, for example, Kindt et al., Kuby Immunology, the 6th edition, W.H.Freeman and Co., page 91 (2007).) single VH or VL domains can be enough to assign antigen-binding specificity.In addition, It can be used with reference to the antibody of specific antigen to be self-bonded the separation of the VH or VL domains of the antibody of the antigen to screen complementary VL respectively Or the library in VH domains.See, for example, Portolano et al., J.Immunol.150：880-887(1993)；Clarkson et al., Nature 352：624-628(1991).
" people shares framework " is residual for the amino acid most often occurred in human immunoglobulin(HIg) VL or VH frame sequence selected by expression The framework of base.In general, human immunoglobulin(HIg) VL or VH sequences are selected from the subgroup of variable domain sequence.In general, sequence Group is the Sequences of Proteins of Immunological Interest such as Kabat et al., the 5th edition, NIH Publication 91-3242, Bethesda MD (1991), the subgroup in the 1-3 volumes.In some embodiments, for VL, subgroup are such as Kabat et al., the subgroup κ I in being same as above.In some embodiments, for VH, subgroup is such as Kabat People, the subgroup III in being same as above.
" humanization " antibody refers to embedding comprising the amino acid residue from inhuman HVR and the amino acid residue from people FR Close antibody.In certain embodiments, humanized antibody is by comprising the substantially all of at least one and usual two variable domains, Wherein completely or generally whole HVR (such as CDR) both correspond to the HVR of non-human antibody, and completely or generally whole FR are equal Corresponding to the FR of human antibody.Humanized antibody can optionally include at least a portion of the antibody constant region from human antibody. " humanization form " of antibody (such as non-human antibody) refers to the antibody for having undergone humanization.
Term " hypervariable region " or " HVR " as used herein refer to the high change (" complementary determining region " of sequence in antibody variable domains Or " CDR ") and/or formed structure on sharp outline ring (" hypervariable loop ") and/or containing antigen contact residue, (" antigen touches Point ") each region.In general, antibody includes six HVR：Three in VH (H1, H2, H3), and three VL (L1, L2, L3) in.This paper exemplary HVR includes：
(a) amino acid residue 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2) are appeared in With hypervariable loop (Chothia and Lesk, the J.Mol.Biol.196 at 96-101 (H3) place：901-917(1987))；
(b) amino acid residue 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2) are appeared in With CDR (Kabat et al., Sequences of Proteins of Immunological at 95-102 (H3) place Interest, the 5th edition Public Health Department, NIH, Bethesda, MD (1991))；
(c) amino acid residue 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 are appeared in (H2) and 93-101 (H3) place antigen contact (MacCallum et al. J.Mol.Biol.262：732-745(1996))；With
(d) combination of (a), (b) and/or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3) and 94-102 (H3).
Unless otherwise instructed, otherwise herein, according to Kabat et al., ibid to the HVR residues in variable domain and other Residue (such as FR residues) is numbered.
" immunoconjugates " are to be combined anti-with one or more heterologous molecules, including but not limited to cytotoxic agent Body.
" individual " or " subject " is mammal.Mammal include but is not limited to domestic animal (such as ox, sheep, Cat, dog and horse), primate (such as people and non-human primate, such as monkey), rabbit and rodent (such as mouse and Rat).In certain embodiments, individual or subject behave.
" separated " antibody is the antibody separated with the component of its natural surroundings.In some embodiments, antibody Purifying reaches purity more than 95% or 99%, and such as example, by electrophoresis, (such as SDS-PAGE, isoelectric focusing (IEF), capillary are electric Swimming method) or chromatography (such as ion exchange or anti-phase HPLC) determined.For assess antibody purity method summary referring to Such as Flatman et al., J.Chromatogr.B 848：79-87(2007).
" separated " nucleic acid refers to the nucleic acid molecules separated with the component of its natural surroundings.Separated nucleic acid includes Nucleic acid molecules contained in the cell of nucleic acid molecules are usually contained, but the nucleic acid molecules are present in outside chromosome or in difference At the chromosome position of its native chromosomal sites.
" the separated nucleic acid for encoding anti-Tau antibody " refer to encoding antibody heavy and light chain (or its fragment) one kind or Such nucleic acid molecules in multiple nucleic acid molecules, including single carrier or carrier out of the ordinary and be present in host cell one or Such nucleic acid molecules of multiple opening positions.
Term " monoclonal antibody " as used herein refers to the antibody that the colony of the basically antibody of homogeneity obtains, That is, except possible antibody variants are (such as containing naturally occurring mutation or what is occurred during monoclonal antibody formulation is produced dash forward The antibody of change, such variant typically to exist on a small quantity) beyond, the individual antibody for forming the colony is identical and/or combine identical Epitope.Compared to the polyclonal antibody preparations for generally including the different antibodies for different determinants (epitope), monoclonal antibody Each monoclonal antibody of preparation is for the single determinant on antigen.Therefore, the feature of modifier " monoclonal " instruction antibody Obtained for the antibody population of basically homogeneity, and should not be construed as needing to produce the antibody by any ad hoc approach.Lift Example for, monoclonal antibody used according to the invention can be made by multiple technologies, including but not limited to hybridoma method, The transgenic animals of recombinant DNA method, phage display method and utilization containing all or part of human immunoglobulin gene's seat Method, such method and other exemplary methods for manufacturing monoclonal antibody described herein.
" exposed antibody " refers to the antibody not combined with heterologous moiety (for example, cytotoxic moieties) or radioactive label.It is naked Antibody can exist with pharmaceutical dosage forms.
" primary antibody " refers to the naturally occurring immunoglobulin molecules with different structure.For example, primary IgG Antibody is about 150, the miscellaneous tetramer glycoprotein of 000 dalton, and it is identical by two identical light chains of disulfide bond bond and two Heavy chain is formed.From N-terminal to C-terminal, each heavy chain has variable region (VH), also referred to as variable heavy chain domain or heavy chain variable domain, then for Three constant domains (CH1, CH2 and CH3).Similarly, from N-terminal to C-terminal, each light chain has variable region (VL), can also referred to as lighten Chain domain or light-chain variable domain, it is then constant light (CL) domain.The light chain of antibody can be returned based on the amino acid sequence of its constant domain For one kind in two types, referred to as κ and λ.
To refer to the specification being typically included in the commercial packing of therapeutic products, it contains term " package insert " On indication, usage, dosage, administration, combination treatment, contraindication and/or the warning relevant with using such therapeutic products Information.
It is defined as comparing reference polypeptide relative to " amino acid sequence identity percentage (%) " of reference polypeptide sequence Sequence and candidate sequence and after introducing gap if necessary to reach maximal sequence homogeneity percentage, and conservative is not being taken In the case that generation is considered as a part for sequence identity, have together with the amino acid residue in reference polypeptide sequence in candidate sequence The percentage of the amino acid residue of one property.The comparison of purpose for determining amino acid sequence identity percentage can be with this area Technical ability in the range of various modes reach, such as using computer software obtained by disclosure, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software.Those skilled in the art can determine that the suitable parameter for aligned sequences, including Reach high specific in the total length of institute's comparative sequences to required any algorithm.However, for the purposes herein, use sequence Compare computer program ALIGN-2 and produce amino acid sequence identity % values.ALIGN-2 sequences compare computer program by Genentech, Inc. are created, and source code is filed in U.S. Copyright Office (U.S.Copyright with user's file Office), Washington D.C., 20559, it is registered in U.S. Copyright Office with S. Copyright registration number TXU510087. ALIGN-2 programs can disclose and be obtained from Genentech, Inc., South San Francisco, California, or can be from source generation Code is write.ALIGN-2 programs can be used for UNIX operating system through writing, including digital UNIX V4.0D.All sequences compare ginseng Number is by ALIGN-2 program settings and does not change.
Using ALIGN-2 carry out amino acid sequence compare in the case of, give amino acid sequence A relative to, with or pin To give amino acid sequence B amino acid sequence identity % (or its can be expressed as having with given amino acid sequence B or The given amino acid sequence A for including certain amino acid sequence identity %) it is calculated as below：
100 are multiplied by a point rate X/Y
Wherein X is to be chosen as the amino acid that unanimously matches by alignment programs ALIGN-2 in A compares with B program The number of residue, and wherein Y is the total number of the amino acid residue in B.It will be appreciated that in amino acid sequence A length and amino In the case of acid sequence B length is unequal, A relative to B amino acid sequence identity % and B relative to A amino acid sequence Row homogeneity % will be unequal.Unless in addition specific statement, otherwise all amino acid sequence identity % values used herein be Obtained as just described in paragraph using ALIGN-2 computer programs.
Term " pharmaceutical preparation " refers to that be in form allows the bioactivity of active component contained therein effectively to play, and not Preparation containing the additional component that the subject of administration is had to unacceptable toxicity to preparation.
" pharmaceutically acceptable carrier " refers to the composition nontoxic to subject in pharmaceutical preparation in addition to the active ingredient (s. Pharmaceutically acceptable carrier includes but is not limited to buffer, excipient, stabilizer or preservative.
Unless otherwise instructed, otherwise as used herein, term " Tau " refers to come from any vertebrate origin, including feeds Newborn animal, such as primate (such as people) and any primary Tau albumen of rodent (such as mouse and rat).The art Language covers " total length " the undressed Tau and any type of Tau as caused by the processing in the cell.The term is also contained Cover naturally occurring Tau variants, such as splice variant or allele variant.
As used herein, term " pTau " refers to that wherein serine, threonine or tyrosine residue are passed through by protein kinase The phosphate groups of addition covalently bonded and the Tau of phosphorylation.In some embodiments, pTau is on serine or in Soviet Union's ammonia Phosphorylation on sour residue.In some embodiments, serines of the pTau at position 409 and/or the serine at position 404 Upper phosphorylation.In some embodiments, phosphorylated on serine of the pTau at position 409.
As used herein, " soluble T au " or " soluble T au albumen " refer to the protein consisted of to term： Tau albumen/the peptide monomer or Tau samples peptide/protein that are completely dissolved or Tau peptides/protein through modifying or truncating or Tau peptides/ Other derivatives and Tau protein oligomers of protein monomers." soluble T au " is particularly intended to exclude neurofibrillary tangles (NFT).
As used herein, term " insoluble Tau " refer to multiple aggregations Tau peptide or protein matter monomers or Tau samples peptide/ Protein or Tau peptides/protein or other derivatives of Tau peptides/protein through modifying or truncating, it forms body outside water In property medium and oligomerization insoluble (more particularly in brain) in mammal or human body in vivo or paradigmatic structure；It is but outstanding It refers to the Tau monomers of multiple aggregations or Tau peptides/protein through modifying or truncating or derivatives thereof, and it is moved in lactation respectively It is insoluble (more particularly in brain) in thing or human body.In particular, " insoluble Tau " includes neurofibrillary tangles (NFT)。
As used herein, " monomer Tau " or " Tau monomers " refer to be completely dissolved in an aqueous medium and answered without aggregation term The Tau albumen of compound.
As used herein, term " aggregation Tau ", " oligomerization Tau " and " Tau oligomers " refer to multiple aggregations Tau peptides or Other of protein monomers or Tau samples peptide/protein or Tau peptides/protein through modifying or truncating or Tau peptides/protein Derivative, it forms external in an aqueous medium and insoluble (more particularly in brain) in mammal or human body in vivo Or solvable oligomerization or paradigmatic structure；But refer in particular to the Tau monomers of multiple aggregations or Tau peptides/albumen through modifying or truncating Matter or derivatives thereof, it is insoluble or solvable (more particularly in brain) in mammal or human body respectively.
" pTau PHF ", " PHF " and " conjugate spirals fibril " are used synonymously herein and referred to in electronics term Visible 160nm is periodically wound in the fibril pair of spiral in microexamination.Width changes between 10 and 22nm.PHF is Dominance structure in the neurofibrillary tangles and neuropil thread of Alzheimer disease (AD).PHF be also shown in some but And the not all malnutritive neural process related to neuritic plaques.PHF key component is the micro-pipe of peroxophosphoric acid form Related protein tau.PHF partly can be made up of the Tau albumen of the antiparallel peroxophosphoric acid of disulfide bond.PHF Tau can Clip 20 amino acid residues of its C-terminal.The potential mechanism that PHF is formed is not known, but Tau peroxophosphoric acidization can make itself and micro-pipe point From so as to increase the soluble T au set that can form PHF on the inside of neuron therefrom.
As used herein, " treat (treatment) " (and its grammatical variants, such as " treat (treat) " or " control Treat (treating) ") refer to clinical intervention with attempt change institute treatment individual natural history, and can be realization prevent or face Carried out in the bed pathology course of disease.Required therapeutic action includes but is not limited to prevention disease generation or recurrence, relief of symptoms, mitigation Any directly or indirectly pathological consequences, prevention metastasis of cancer, reduction disease process speed, improvement or the mitigation disease state of disease With alleviation or improvement prognosis.In some embodiments, antibody of the invention is used to postpone disease development or slows down disease process.
Term " early stage Alzheimer disease " as used herein or " early stage AD " (such as " is diagnosed as with early stage AD Patient " or " patient for suffering from early stage AD " include patient with the mild cognitive impairment (such as memory defects) for being attributed to AD and Patient with AD biomarkers, such as amyloid positive patient.
Term " mild Alzheimer's disease " as used herein or " mild AD " (such as " be diagnosed as with mild AD Patient ") refer to be characterized in that the AD stages that MMSE scorings are 20 to 26.
Term " slightly to moderate Alzheimer's disease " as used herein is covered slight with " slightly to moderate AD " Both AD are spent, and are characterized in that MMSE scorings are 18 to 26.
Term " moderate Alzheimer's disease " as used herein or " moderate AD " (such as " be diagnosed as with moderate AD Patient ") refer to be characterized in that the AD stages that MMSE scorings are 18 to 19.
Term " MMSE " refers to mini mental state examination (Mini Mental State Examination), and it is provided Scoring between 1 and 30.Referring to Folstein et al., 1975, J.Psychiatr.Res.12：189-98.26 and 26 with Under scoring be generally viewed as indicate defect.There is the individual of relatively low scoring relative to another, the upper numeric ratings of MMSE are lower, institute The defect or obstacle of the patient of test is bigger.The increase of MMSE scorings may indicate that the improvement of patient condition, and what MMSE scored subtracts The deterioration of patient condition is may indicate that less.
As used herein, term " carrier " refers to a kind of nucleic acid molecules, and it can propagate its another nucleic acid connected Molecule.The term is including the carrier in self-replicating nucleic acid structure and is incorporated in the genome for the host cell for having been introduced into it Carrier.Some carriers can guide the expression of its nucleic acid being operably connected.Examples of such carriers is referred to herein as " expression load Body ".
II. composition and method
Antibody with reference to Tau is provided.In some embodiments, antibody binding Tau of the invention, with reference to monomer Tau, widow Poly- Tau, non-phosphorylating Tau and phosphorylation Tau.In some embodiments, antibody binding of the invention is in the ammonia into acquaintance Tau Epitope in base acid 2 to 24.In some embodiments, antibody binding of the invention is in the epitope in Tau amino acid 2 to 24, And combine monomer Tau, oligomerization Tau, non-phosphorylating Tau and phosphorylation Tau.In some embodiments, antibody binding has sequence Arrange AEPRQEFEVMEDHAGTYGLGDRK (SEQ ID NO：Or the people Tau epitope that is made from it 2).In some embodiments In, antibody binding has sequence AEPRQEFDVMEDHAGTYGLGDRK (SEQ ID NO：Or the machin Tau that is made from it 4) Epitope.In some embodiments, antibody binding has sequence AEPRQEFEVMEDHAGTYGLGDRK (SEQ ID NO：2) Or the people Tau being made from it epitope and there is sequence AEPRQEFDVMEDHAGTYGLGDRK (SEQ ID NO：4) or by its group Into machin Tau epitope.In some embodiments, antibody binding of the invention in the amino acid/11 9 into acquaintance Tau to 33rd, the epitope in 19 to 42,37 to 51,100 to 114,118 to 132 or 172 to 177.In some embodiments, it is of the invention Antibody binding in the amino acid/11 9 to 33,19 to 42,37 to 51,100 to 114,118 to 132 or 172 to 177 into acquaintance Tau Interior epitope, and combine monomer Tau, oligomerization Tau, non-phosphorylating Tau and phosphorylation Tau.
The antibody of the present invention is applied to for example diagnose or treat neurodegenerative disorders.
A. exemplary anti-Tau antibody
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) include and be selected from SEQ ID NO：12nd, the HVR-H1 of 22,282,292 and 342 amino acid sequence；(b) include Selected from SEQ ID NO：13rd, the HVR-H2 of 23,283,293 and 343 amino acid sequence；(c) include and be selected from SEQ ID NO：14、 24th, the HVR-H3 of 284,294 and 344 amino acid sequence；(d) include and be selected from SEQ ID NO：15th, 25,285,295,345 and The HVR-L1 of 468 to 556 amino acid sequence；(e) include and be selected from SEQ ID NO：16th, 26,286,296 and 346 amino acid The HVR-L2 of sequence；Include and be selected from SEQ ID NO (f)：17th, the HVR-L3 of 27,287,297 and 347 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 342 amino acid sequence；(b) SEQ ID NO are included：343 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 344 amino acid sequence；(d) SEQ ID NO are included：345 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 346 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 347 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) include and be selected from SEQ ID NO：The HVR-H1 of 72 and 302 amino acid sequence；(b) include and be selected from SEQ ID NO：The HVR-H2 of 73 and 303 amino acid sequence；(c) include and be selected from SEQ ID NO：The HVR- of 74 and 304 amino acid sequence H3；(d) include and be selected from SEQ ID NO：The HVR-L1 of 75 and 305 amino acid sequence；(e) include and be selected from SEQ ID NO：76 Hes The HVR-L2 of 306 amino acid sequence；Include and be selected from SEQ ID NO (f)：The HVR-L3 of 77 and 307 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) include and be selected from SEQ ID NO：82nd, the HVR-H1 of 312,322 and 332 amino acid sequence；(b) comprising choosing From SEQ ID NO：83rd, the HVR-H2 of 313,323 and 333 amino acid sequence；(c) include and be selected from SEQ ID NO：84、314、 The HVR-H3 of 324 and 334 amino acid sequence；(d) include and be selected from SEQ ID NO：85th, 315,325 and 335 amino acid sequence HVR-L1；(e) include and be selected from SEQ ID NO：86th, the HVR-L2 of 316,326 and 336 amino acid sequence；Comprising choosing (f) From SEQ ID NO：87th, the HVR-L3 of 317,327 and 337 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 32 amino acid sequence；(b) SEQ ID NO are included：33 amino acid The HVR-H2 of sequence；(c) SEQ ID NO are included：The HVR-H3 of 34 amino acid sequence；(d) SEQ ID NO are included：35 ammonia The HVR-L1 of base acid sequence；(e) SEQ ID NO are included：The HVR-L2 of 36 amino acid sequence；Include SEQ ID NO (f)： The HVR-L3 of 37 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 42 amino acid sequence；(b) SEQ ID NO are included：43 amino acid The HVR-H2 of sequence；(c) SEQ ID NO are included：The HVR-H3 of 44 amino acid sequence；(d) SEQ ID NO are included：45 ammonia The HVR-L1 of base acid sequence；(e) SEQ ID NO are included：The HVR-L2 of 46 amino acid sequence；Include SEQ ID NO (f)： The HVR-L3 of 47 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 52 amino acid sequence；(b) SEQ ID NO are included：53 amino acid The HVR-H2 of sequence；(c) SEQ ID NO are included：The HVR-H3 of 54 amino acid sequence；(d) SEQ ID NO are included：55 ammonia The HVR-L1 of base acid sequence；(e) SEQ ID NO are included：The HVR-L2 of 56 amino acid sequence；Include SEQ ID NO (f)： The HVR-L3 of 57 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 62 amino acid sequence；(b) SEQ ID NO are included：63 amino acid The HVR-H2 of sequence；(c) SEQ ID NO are included：The HVR-H3 of 64 amino acid sequence；(d) SEQ ID NO are included：65 ammonia The HVR-L1 of base acid sequence；(e) SEQ ID NO are included：The HVR-L2 of 66 amino acid sequence；Include SEQ ID NO (f)： The HVR-L3 of 67 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 72 amino acid sequence；(b) SEQ ID NO are included：73 amino acid The HVR-H2 of sequence；(c) SEQ ID NO are included：The HVR-H3 of 74 amino acid sequence；(d) SEQ ID NO are included：75 ammonia The HVR-L1 of base acid sequence；(e) SEQ ID NO are included：The HVR-L2 of 76 amino acid sequence；Include SEQ ID NO (f)： The HVR-L3 of 77 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 82 amino acid sequence；(b) SEQ ID NO are included：83 amino acid The HVR-H2 of sequence；(c) SEQ ID NO are included：The HVR-H3 of 84 amino acid sequence；(d) SEQ ID NO are included：85 ammonia The HVR-L1 of base acid sequence；(e) SEQ ID NO are included：The HVR-L2 of 86 amino acid sequence；Include SEQ ID NO (f)： The HVR-L3 of 87 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 92 amino acid sequence；(b) SEQ ID NO are included：93 amino acid The HVR-H2 of sequence；(c) SEQ ID NO are included：The HVR-H3 of 94 amino acid sequence；(d) SEQ ID NO are included：95 ammonia The HVR-L1 of base acid sequence；(e) SEQ ID NO are included：The HVR-L2 of 96 amino acid sequence；Include SEQ ID NO (f)： The HVR-L3 of 97 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 102 amino acid sequence；(b) SEQ ID NO are included：103 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 104 amino acid sequence；(d) SEQ ID NO are included：105 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 106 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 107 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 112 amino acid sequence；(b) SEQ ID NO are included：113 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 114 amino acid sequence；(d) SEQ ID NO are included：115 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 116 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 117 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 122 amino acid sequence；(b) SEQ ID NO are included：123 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 124 amino acid sequence；(d) SEQ ID NO are included：125 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 126 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 127 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 132 amino acid sequence；(b) SEQ ID NO are included：133 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 134 amino acid sequence；(d) SEQ ID NO are included：135 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 136 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 137 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 142 amino acid sequence；(b) SEQ ID NO are included：143 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 144 amino acid sequence；(d) SEQ ID NO are included：145 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 146 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 147 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 152 amino acid sequence；(b) SEQ ID NO are included：153 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 154 amino acid sequence；(d) SEQ ID NO are included：155 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 156 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 157 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 162 amino acid sequence；(b) SEQ ID NO are included：163 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 164 amino acid sequence；(d) SEQ ID NO are included：165 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 166 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 167 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 172 amino acid sequence；(b) SEQ ID NO are included：173 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 174 amino acid sequence；(d) SEQ ID NO are included：175 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 176 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 177 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 182 amino acid sequence；(b) SEQ ID NO are included：183 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 184 amino acid sequence；(d) SEQ ID NO are included：185 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 186 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 187 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 192 amino acid sequence；(b) SEQ ID NO are included：193 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 194 amino acid sequence；(d) SEQ ID NO are included：195 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 196 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 197 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 202 amino acid sequence；(b) SEQ ID NO are included：203 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 204 amino acid sequence；(d) SEQ ID NO are included：205 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 206 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 207 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 212 amino acid sequence；(b) SEQ ID NO are included：213 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 214 amino acid sequence；(d) SEQ ID NO are included：215 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 216 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 217 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 222 amino acid sequence；(b) SEQ ID NO are included：223 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 224 amino acid sequence；(d) SEQ ID NO are included：225 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 226 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 227 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 232 amino acid sequence；(b) SEQ ID NO are included：233 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 234 amino acid sequence；(d) SEQ ID NO are included：235 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 236 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 237 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 242 amino acid sequence；(b) SEQ ID NO are included：243 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 244 amino acid sequence；(d) SEQ ID NO are included：245 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 246 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 247 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 252 amino acid sequence；(b) SEQ ID NO are included：253 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 254 amino acid sequence；(d) SEQ ID NO are included：255 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 256 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 257 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 262 amino acid sequence；(b) SEQ ID NO are included：263 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 264 amino acid sequence；(d) SEQ ID NO are included：265 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 266 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 267 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 272 amino acid sequence；(b) SEQ ID NO are included：273 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 274 amino acid sequence；(d) SEQ ID NO are included：275 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 276 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 277 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 282 amino acid sequence；(b) SEQ ID NO are included：283 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 284 amino acid sequence；(d) SEQ ID NO are included：285 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 286 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 287 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 292 amino acid sequence；(b) SEQ ID NO are included：293 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 294 amino acid sequence；(d) SEQ ID NO are included：295 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 296 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 297 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 302 amino acid sequence；(b) SEQ ID NO are included：303 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 304 amino acid sequence；(d) SEQ ID NO are included：305 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 306 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 307 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 312 amino acid sequence；(b) SEQ ID NO are included：313 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 314 amino acid sequence；(d) SEQ ID NO are included：315 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 316 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 317 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 322 amino acid sequence；(b) SEQ ID NO are included：323 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 324 amino acid sequence；(d) SEQ ID NO are included：325 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 326 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 327 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two, three, four, five or six be selected from Following HVR：(a) SEQ ID NO are included：The HVR-H1 of 332 amino acid sequence；(b) SEQ ID NO are included：333 amino The HVR-H2 of acid sequence；(c) SEQ ID NO are included：The HVR-H3 of 334 amino acid sequence；(d) SEQ ID NO are included：335 Amino acid sequence HVR-L1；(e) SEQ ID NO are included：The HVR-L2 of 336 amino acid sequence；Include SEQ ID (f) NO：The HVR-L3 of 337 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap Containing selected from SEQ ID NO：12nd, the HVR-H1 of 22,282,292 and 342 amino acid sequence；(b) include and be selected from SEQ ID NO： 13rd, the HVR-H2 of 23,283,293 and 343 amino acid sequence；Include and be selected from SEQ ID NO (c)：14th, 24,284,294 and The HVR-H3 of 344 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) and is selected from SEQ ID NO： 12nd, the HVR-H1 of 22,282,292 and 342 amino acid sequence；(b) include and be selected from SEQ ID NO：13rd, 23,283,293 and The HVR-H2 of 343 amino acid sequence；Include and be selected from SEQ ID NO (c)：14th, 24,284,294 and 344 amino acid sequence HVR-H3.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 342 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 343 amino acid sequence；Include SEQ ID NO (c)：344 amino acid sequence The HVR-H3 of row.In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) Include SEQ ID NO：The HVR-H1 of 342 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 343 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 344 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap Containing selected from SEQ ID NO：The HVR-H1 of 72 and 302 amino acid sequence；(b) include and be selected from SEQ ID NO：73 and 303 ammonia The HVR-H2 of base acid sequence；Include and be selected from SEQ ID NO (c)：The HVR-H3 of 74 and 304 amino acid sequence.In some realities Apply in scheme, anti-Tau antibody includes comprising (a) and is selected from SEQ ID NO：The HVR-H1 of 72 and 302 amino acid sequence；(b) wrap Containing selected from SEQ ID NO：The HVR-H2 of 73 and 303 amino acid sequence；Include and be selected from SEQ ID NO (c)：74 and 304 The HVR-H3 of amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap Containing selected from SEQ ID NO：82nd, the HVR-H1 of 312,322 and 332 amino acid sequence；(b) include and be selected from SEQ ID NO：83、 313rd, the HVR-H2 of 323 and 333 amino acid sequence；Include and be selected from SEQ ID NO (c)：84th, 314,324 and 334 amino The HVR-H3 of acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) and is selected from SEQ ID NO：82、312、322 With the HVR-H1 of 332 amino acid sequence；(b) include and be selected from SEQ ID NO：83rd, 313,323 and 333 amino acid sequence HVR-H2；Include and be selected from SEQ ID NO (c)：84th, the HVR-H3 of 314,324 and 334 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 32 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 33 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 34 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-H1 of 32 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 33 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 34 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 42 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 43 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 44 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-H1 of 42 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 43 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 44 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 52 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 53 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 54 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-H1 of 52 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 53 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 54 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 62 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 63 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 64 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-H1 of 62 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 63 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 64 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 72 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 73 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 74 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-H1 of 72 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 73 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 74 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 82 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 83 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 84 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-H1 of 82 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 83 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 84 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 92 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 93 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 94 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-H1 of 92 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 93 amino acid sequence；With (c) SEQ ID NO are included：The HVR-H3 of 94 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 102 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 103 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 104 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 102 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 103 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 104 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 112 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 113 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 114 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 112 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 113 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 114 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 122 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 123 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 124 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 122 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 123 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 124 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 132 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 133 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 134 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 132 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 133 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 134 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 142 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 143 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 144 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 142 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 143 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 144 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 152 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 153 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 154 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 152 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 153 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 154 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 162 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 163 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 164 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 162 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 163 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 164 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 172 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 173 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 174 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 172 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 173 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 174 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 182 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 183 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 184 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 182 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 183 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 184 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 192 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 193 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 194 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 192 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 193 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 194 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 202 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 203 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 204 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 202 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 203 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 204 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 212 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 213 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 214 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 212 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 213 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 214 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 222 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 223 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 224 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 222 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 223 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 224 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 232 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 233 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 234 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 232 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 233 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 234 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 242 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 243 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 244 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 242 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 243 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 244 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 252 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 253 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 254 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 252 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 253 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 254 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 262 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 263 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 264 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 262 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 263 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 264 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 272 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 273 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 274 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 272 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 273 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 274 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 282 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 283 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 284 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 282 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 283 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 284 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 292 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 293 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 294 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 292 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 293 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 294 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 302 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 303 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 304 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 302 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 303 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 304 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 312 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 313 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 314 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 312 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 313 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 314 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 322 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 323 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 324 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 322 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 323 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 324 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-H1 of 332 amino acid sequence；(b) SEQ ID NO are included：The HVR-H2 of 333 amino acid sequence； Include SEQ ID NO (c)：The HVR-H3 of 334 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-H1 of 332 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 333 amino acid sequence H2；Include SEQ ID NO (c)：The HVR-H3 of 334 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap Containing selected from SEQ ID NO：15th, the HVR-L1 of 25,285,295,345 and 468 to 556 amino acid sequence；(b) include and be selected from SEQ ID NO：16th, the HVR-L2 of 26,286,296 and 346 amino acid sequence；Include and be selected from SEQ ID NO (c)：17、 27th, the HVR-L3 of 287,297 and 347 amino acid sequence.In some embodiments, anti-Tau antibody is included comprising (a) and is selected from SEQ ID NO：15th, the HVR-L1 of 25,285,295,345 and 468 to 556 amino acid sequence；(b) include and be selected from SEQ ID NO：16th, the HVR-L2 of 26,286,296 and 346 amino acid sequence；Include and be selected from SEQ ID NO (c)：17、27、287、 The HVR-L3 of 297 and 347 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 345 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 346 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 347 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 345 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 346 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 347 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap Containing selected from SEQ ID NO：The HVR-L1 of 75 and 305 amino acid sequence；(b) include and be selected from SEQ ID NO：76 and 306 ammonia The HVR-L2 of base acid sequence；Include and be selected from SEQ ID NO (c)：The HVR-L3 of 77 and 307 amino acid sequence.In some realities Apply in scheme, anti-Tau antibody includes comprising (a) and is selected from SEQ ID NO：The HVR-L1 of 75 and 305 amino acid sequence；(b) wrap Containing selected from SEQ ID NO：The HVR-L2 of 76 and 306 amino acid sequence；Include and be selected from SEQ ID NO (c)：77 and 307 The HVR-L3 of amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap Containing selected from SEQ ID NO：85th, the HVR-L1 of 315,325 and 335 amino acid sequence；(b) include and be selected from SEQ ID NO：86、 316th, the HVR-L2 of 326 and 336 amino acid sequence；Include and be selected from SEQ ID NO (c)：87th, 317,327 and 337 amino The HVR-L3 of acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) and is selected from SEQ ID NO：85、315、325 With the HVR-L1 of 335 amino acid sequence；(b) include and be selected from SEQ ID NO：86th, 316,326 and 336 amino acid sequence HVR-L2；Include and be selected from SEQ ID NO (c)：87th, the HVR-L3 of 317,327 and 337 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 35 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 36 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 37 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-L1 of 35 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 36 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 37 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 45 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 46 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 47 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-L1 of 45 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 46 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 47 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 55 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 56 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 57 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-L1 of 55 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 56 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 57 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 65 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 66 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 67 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-L1 of 65 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 66 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 67 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 75 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 76 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 77 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-L1 of 75 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 76 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 77 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 85 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 86 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 87 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-L1 of 85 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 86 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 87 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 95 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 96 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 97 amino acid sequence.In some embodiments, anti-Tau antibody includes comprising (a) SEQ ID NO：The HVR-L1 of 95 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 96 amino acid sequence；With (c) SEQ ID NO are included：The HVR-L3 of 97 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 105 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 106 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 107 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 105 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 106 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 107 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 115 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 116 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 117 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 115 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 116 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 117 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 125 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 126 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 127 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 125 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 126 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 127 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 135 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 136 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 137 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 135 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 136 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 137 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 145 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 146 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 147 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 145 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 146 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 147 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 155 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 156 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 157 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 155 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 156 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 157 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 165 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 166 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 167 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 165 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 166 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 167 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 175 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 176 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 177 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 175 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 176 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 177 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 185 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 186 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 187 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 185 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 186 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 187 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 195 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 196 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 197 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 195 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 196 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 197 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 205 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 206 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 207 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 205 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 206 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 207 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 215 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 216 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 217 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 215 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 216 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 217 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 225 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 226 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 227 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 225 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 226 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 227 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 235 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 236 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 237 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 235 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 236 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 237 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 245 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 246 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 247 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 245 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 246 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 247 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 255 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 256 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 257 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 255 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 256 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 257 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 265 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 266 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 267 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 265 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 266 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 267 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 275 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 276 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 277 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 275 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 276 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 277 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 285 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 286 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 287 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 285 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 286 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 287 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 295 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 296 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 297 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 295 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 296 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 297 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 305 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 306 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 307 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 305 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 306 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 307 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 315 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 316 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 317 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 315 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 316 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 317 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 325 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 326 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 327 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 325 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 326 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 327 amino acid sequence.
In some embodiments, anti-Tau antibody include it is at least one, two or three be selected from following HVR：(a) wrap The NO of ID containing SEQ：The HVR-L1 of 335 amino acid sequence；(b) SEQ ID NO are included：The HVR-L2 of 336 amino acid sequence； Include SEQ ID NO (c)：The HVR-L3 of 337 amino acid sequence.In some embodiments, anti-Tau antibody includes (a) Include SEQ ID NO：The HVR-L1 of 335 amino acid sequence；(b) SEQ ID NO are included：The HVR- of 336 amino acid sequence L2；Include SEQ ID NO (c)：The HVR-L3 of 337 amino acid sequence.
In some embodiments, anti-Tau antibody includes comprising (a) and is selected from SEQ ID NO：12nd, 22,282,292 and 342 Amino acid sequence HVR-H1；(b) include and be selected from SEQ ID NO：13rd, 23,283,293 and 343 amino acid sequence HVR-H2；(c) include and be selected from SEQ ID NO：14th, the HVR-H3 of 24,284,294 and 344 amino acid sequence；(d) comprising choosing From SEQ ID NO：15th, the HVR-L1 of 25,285,295,345 and 468 to 556 amino acid sequence；(e) include and be selected from SEQ ID NO：16th, the HVR-L2 of 26,286,296 and 346 amino acid sequence；Include and be selected from SEQ ID NO (f)：17、27、287、 The HVR-L3 of 297 and 347 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 342 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 343 amino acid sequence；(c) SEQ ID NO are included：344 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 345 amino acid sequence；(e) SEQ ID NO are included：346 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 347 amino acid sequence.
In some embodiments, anti-Tau antibody includes comprising (a) and is selected from SEQ ID NO：72 and 302 amino acid sequence The HVR-H1 of row；(b) include and be selected from SEQ ID NO：The HVR-H2 of 73 and 303 amino acid sequence；(c) include and be selected from SEQ ID NO：The HVR-H3 of 74 and 304 amino acid sequence；(d) include and be selected from SEQ ID NO：The HVR- of 75 and 305 amino acid sequence L1；(e) include and be selected from SEQ ID NO：The HVR-L2 of 76 and 306 amino acid sequence；Include and be selected from SEQ ID NO (f)：77 With the HVR-L3 of 307 amino acid sequence.
In some embodiments, anti-Tau antibody includes comprising (a) and is selected from SEQ ID NO：82nd, 312,322 and 332 The HVR-H1 of amino acid sequence；(b) include and be selected from SEQ ID NO：83rd, the HVR-H2 of 313,323 and 333 amino acid sequence； (c) include and be selected from SEQ ID NO：84th, the HVR-H3 of 314,324 and 334 amino acid sequence；(d) include and be selected from SEQ ID NO：85th, the HVR-L1 of 315,325 and 335 amino acid sequence；(e) include and be selected from SEQ ID NO：86th, 316,326 and 336 The HVR-L2 of amino acid sequence；Include and be selected from SEQ ID NO (f)：87th, the HVR- of 317,327 and 337 amino acid sequence L3。
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 32 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 33 amino acid sequence；(c) SEQ ID NO are included：34 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 35 amino acid sequence；(e) SEQ ID NO are included：36 amino acid sequence The HVR-L2 of row；Include SEQ ID NO (f)：The HVR-L3 of 37 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 42 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 43 amino acid sequence；(c) SEQ ID NO are included：44 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 45 amino acid sequence；(e) SEQ ID NO are included：46 amino acid sequence The HVR-L2 of row；Include SEQ ID NO (f)：The HVR-L3 of 47 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 52 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 53 amino acid sequence；(c) SEQ ID NO are included：54 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 55 amino acid sequence；(e) SEQ ID NO are included：56 amino acid sequence The HVR-L2 of row；Include SEQ ID NO (f)：The HVR-L3 of 57 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 62 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 63 amino acid sequence；(c) SEQ ID NO are included：64 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 65 amino acid sequence；(e) SEQ ID NO are included：66 amino acid sequence The HVR-L2 of row；Include SEQ ID NO (f)：The HVR-L3 of 67 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 72 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 73 amino acid sequence；(c) SEQ ID NO are included：74 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 75 amino acid sequence；(e) SEQ ID NO are included：76 amino acid sequence The HVR-L2 of row；Include SEQ ID NO (f)：The HVR-L3 of 77 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 82 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 83 amino acid sequence；(c) SEQ ID NO are included：84 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 85 amino acid sequence；(e) SEQ ID NO are included：86 amino acid sequence The HVR-L2 of row；Include SEQ ID NO (f)：The HVR-L3 of 87 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 92 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 93 amino acid sequence；(c) SEQ ID NO are included：94 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 95 amino acid sequence；(e) SEQ ID NO are included：96 amino acid sequence The HVR-L2 of row；Include SEQ ID NO (f)：The HVR-L3 of 97 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 102 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 103 amino acid sequence；(c) SEQ ID NO are included：104 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 105 amino acid sequence；(e) SEQ ID NO are included：106 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 107 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 112 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 113 amino acid sequence；(c) SEQ ID NO are included：114 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 115 amino acid sequence；(e) SEQ ID NO are included：116 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 117 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 122 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 123 amino acid sequence；(c) SEQ ID NO are included：124 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 125 amino acid sequence；(e) SEQ ID NO are included：126 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 127 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 132 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 133 amino acid sequence；(c) SEQ ID NO are included：134 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 135 amino acid sequence；(e) SEQ ID NO are included：136 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 137 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 142 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 143 amino acid sequence；(c) SEQ ID NO are included：144 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 145 amino acid sequence；(e) SEQ ID NO are included：146 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 147 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 152 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 153 amino acid sequence；(c) SEQ ID NO are included：154 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 155 amino acid sequence；(e) SEQ ID NO are included：156 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 157 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 162 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 163 amino acid sequence；(c) SEQ ID NO are included：164 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 165 amino acid sequence；(e) SEQ ID NO are included：166 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 167 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 172 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 173 amino acid sequence；(c) SEQ ID NO are included：174 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 175 amino acid sequence；(e) SEQ ID NO are included：176 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 177 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 182 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 183 amino acid sequence；(c) SEQ ID NO are included：184 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 185 amino acid sequence；(e) SEQ ID NO are included：186 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 187 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 192 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 193 amino acid sequence；(c) SEQ ID NO are included：194 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 195 amino acid sequence；(e) SEQ ID NO are included：196 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 197 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 202 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 203 amino acid sequence；(c) SEQ ID NO are included：204 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 205 amino acid sequence；(e) SEQ ID NO are included：206 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 207 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 212 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 213 amino acid sequence；(c) SEQ ID NO are included：214 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 215 amino acid sequence；(e) SEQ ID NO are included：216 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 217 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 222 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 223 amino acid sequence；(c) SEQ ID NO are included：224 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 225 amino acid sequence；(e) SEQ ID NO are included：226 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 227 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 232 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 233 amino acid sequence；(c) SEQ ID NO are included：234 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 235 amino acid sequence；(e) SEQ ID NO are included：236 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 237 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 242 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 243 amino acid sequence；(c) SEQ ID NO are included：244 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 245 amino acid sequence；(e) SEQ ID NO are included：246 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 247 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 252 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 253 amino acid sequence；(c) SEQ ID NO are included：254 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 255 amino acid sequence；(e) SEQ ID NO are included：256 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 257 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 262 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 263 amino acid sequence；(c) SEQ ID NO are included：264 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 265 amino acid sequence；(e) SEQ ID NO are included：266 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 267 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 272 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 273 amino acid sequence；(c) SEQ ID NO are included：274 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 275 amino acid sequence；(e) SEQ ID NO are included：276 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 277 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 282 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 283 amino acid sequence；(c) SEQ ID NO are included：284 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 285 amino acid sequence；(e) SEQ ID NO are included：286 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 287 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 292 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 293 amino acid sequence；(c) SEQ ID NO are included：294 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 295 amino acid sequence；(e) SEQ ID NO are included：296 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 297 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 302 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 303 amino acid sequence；(c) SEQ ID NO are included：304 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 305 amino acid sequence；(e) SEQ ID NO are included：306 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 307 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 312 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 313 amino acid sequence；(c) SEQ ID NO are included：314 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 315 amino acid sequence；(e) SEQ ID NO are included：316 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 317 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 322 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 323 amino acid sequence；(c) SEQ ID NO are included：324 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 325 amino acid sequence；(e) SEQ ID NO are included：326 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 327 amino acid sequence.
In some embodiments, anti-Tau antibody includes SEQ ID NO comprising (a)：The HVR- of 332 amino acid sequence H1；(b) SEQ ID NO are included：The HVR-H2 of 333 amino acid sequence；(c) SEQ ID NO are included：334 amino acid sequence HVR-H3；(d) SEQ ID NO are included：The HVR-L1 of 335 amino acid sequence；(e) SEQ ID NO are included：336 amino The HVR-L2 of acid sequence；Include SEQ ID NO (f)：The HVR-L3 of 337 amino acid sequence.
In any the embodiment above, anti-Tau antibody is humanized antibody.In some embodiments, anti-Tau antibody Include comprising the HVR in such as any the embodiment above and further acceptor people's framework, for example, human immunoglobulin(HIg) framework or People shares framework.
On the other hand, anti-Tau antibody includes and SEQ ID NO：10、20、30、40、50、60、70、80、90、100、 110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、 300th, 310,320,330 or 340 amino acid sequence have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%th, heavy chain variable domain (VH) sequence of 98%, 99% or 100% sequence identity.In certain embodiments, have at least 90%th, the VH sequences of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homogeneity are relative to reference to sequence Row are containing substituted (such as conservative replaces), insertion or missing, but the reservation of the anti-Tau antibody comprising the sequence is combined with Tau Ability.In certain embodiments, in SEQ ID NO：10、20、30、40、50、60、70、80、90、100、110、120、 130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、 320th, 1 to 10 amino acid is amounted in 330 or 340 to be substituted, insert and/or missing.In certain embodiments, substitute, Insertion or missing occur in the area on the outside of HVR (i.e. in FR).Optionally, anti-Tau antibody includes SEQ ID NO：10、20、 30、40、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、220、230、 240th, the VH sequences in 250,260,270,280,290,300,310,320,330 or 340, including repaiied after the translation of the sequence Decorations.In one particular embodiment, VH is selected from following HVR comprising one, two or three：(a) SEQ ID NO are included： 12、22、32、42、52、62、72、82、92、102、112、122、132、142、152、162、172、182、192、202、212、 222nd, the HVR-H1 of 232,242,252,262,272,282,292,302,312,322,332 or 342 amino acid sequence, (b) Include SEQ ID NO：13、23、33、43、53、63、73、83、93、100、113、123、133、143、153、163、173、183、 193rd, 203,213,223,233,243,253,263,273,283,293,303,313,323,333 or 343 amino acid sequence HVR-H2, and (c) include SEQ ID NO：14、24、34、44、54、64、74、84、94、104、114、124、134、144、 154th, 164,174,184,194,204,214,224,234,244,254,264,274,284,294,304,314,324,334 or The HVR-H3 of 344 amino acid sequence.
On the other hand, anti-Tau antibody includes and SEQ ID NO：11、21、31、41、51、61、71、81、91、101、 111、121、131、141、151、161、171、181、191、201、211、221、231、241、251、261、271、281、291、 301st, 311,321,331 or 341 amino acid sequence have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%th, light-chain variable domain (VL) sequence of 98%, 99% or 100% sequence identity.In certain embodiments, have at least 90%th, the VL sequences of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homogeneity are relative to reference to sequence Row are containing substituted (such as conservative replaces), insertion or missing, but the reservation of the anti-Tau antibody comprising the sequence is combined with Tau Ability.In certain embodiments, in SEQ ID NO：11、21、31、41、51、61、71、81、91、101、111、121、 131、141、151、161、171、181、191、201、211、221、231、241、251、261、271、281、291、301、311、 321st, 1 to 10 amino acid is amounted in 331 or 341 to be substituted, insert and/or missing.In certain embodiments, substitute, Insertion or missing occur in the area on the outside of HVR (i.e. in FR).Optionally, anti-Tau antibody includes SEQ ID NO：11、21、 31、41、51、61、71、81、91、101、111、121、131、141、151、161、171、181、191、201、211、221、231、 241st, the VL sequences in 251,261,271,281,291,301,311,321,331 or 341, including repaiied after the translation of the sequence Decorations.In one particular embodiment, VL is selected from following HVR comprising one, two or three：(a) SEQ ID NO are included： 15、25、35、45、55、65、75、85、95、105、115、125、135、145、155、165、175、185、195、205、215、 225th, the HVR-L1 of 235,245,255,265,275,285,295,305,315,325,335 or 345 amino acid sequence, (b) Include SEQ ID NO：16、26、36、46、56、66、76、86、96、106、116、126、136、146、156、166、176、186、 196th, 206,216,226,236,246,266,266,276,286,296,306,316,326,336 or 346 amino acid sequence HVR-L2, and (c) include SEQ ID NO：17、27、37、47、57、67、77、87、97、107、117、127、137、147、 157th, 167,177,187,197,207,217,227,237,247,267,277,277,287,297,307,317,327,337 or The HVR-L3 of 347 amino acid sequence.
On the other hand, there is provided a kind of anti-Tau antibody, wherein the antibody includes any one implementation of confession as mentioned above VH in the scheme and VL in any one embodiment of confession as mentioned above.In some embodiments, antibody includes difference In SEQ ID NO：280 and SEQ ID NO：VH and VL sequences in 281, include the posttranslational modification of those sequences.At some In embodiment, antibody is included respectively in SEQ ID NO：290 and SEQ ID NO：VH and VL sequences in 291, including those The posttranslational modification of sequence.In some embodiments, antibody is included respectively in SEQ ID NO：300 and SEQ ID NO：301 In VH and VL sequences, include the posttranslational modification of those sequences.In some embodiments, antibody is included respectively in SEQ ID NO：310 and SEQ ID NO：VH and VL sequences in 311, include the posttranslational modification of those sequences.In some embodiments In, antibody is included respectively in SEQ ID NO：320 and SEQ ID NO：VH and VL sequences in 321, including those sequences are turned over Modified after translating.In some embodiments, antibody is included respectively in SEQ ID NO：330 and SEQ ID NO：VH in 331 and VL sequences, include the posttranslational modification of those sequences.In some embodiments, antibody is included respectively in SEQ ID NO：340 With SEQ ID NO：VH and VL sequences in 341, include the posttranslational modification of those sequences.
In some embodiments, there is provided a kind of anti-Tau antibody, wherein the antibody includes comprising SEQ ID NO： 348 or SEQ ID NO：The heavy chain of 602 amino acid sequence and include SEQ ID NO：The light chain of 349 amino acid sequence. In some embodiments, there is provided a kind of anti-Tau antibody, wherein the antibody is included by SEQ ID NO：348 or SEQ ID NO： 602 amino acid sequence composition heavy chain and by SEQ ID NO：The light chain of 349 amino acid sequence composition.
On the other hand, the present invention provides a kind of and anti-Tau antibody bindings provided in this article in the antibody of same epitope. For example, in certain embodiments, there is provided with selected from 94B2-C1,125B11-H3,37D3-H9 and hu37D3- H9.v28.A4 antibody binding is in the antibody of same epitope.In certain embodiments, there is provided be incorporated into Tau fragments by SEQ ID NO：The antibody of the epitope of 2 amino acid 2-24 compositions.In certain embodiments, there is provided be incorporated into Tau fragments by SEQ ID NO：The antibody of the epitope of 2 amino acid 7-24 compositions.In certain embodiments, there is provided be incorporated into Tau fragments by SEQ ID NO：The antibody of the epitope of 2 amino acid 7-20 compositions.In certain embodiments, there is provided be incorporated into Tau fragments by SEQ ID NO：The antibody of the epitope of 2 amino acid/11 0-24 compositions.In certain embodiments, there is provided be incorporated into Tau fragments by SEQ ID NO：The antibody of the epitope of 2 amino acid 7-21 compositions.In certain embodiments, there is provided be incorporated into Tau fragments By SEQ ID NO：The antibody of the epitope of 2 amino acid 8-22 compositions.In certain embodiments, there is provided be incorporated into Tau fragments It is interior by SEQ ID NO：The antibody of the epitope of 2 amino acid/11 1-25 compositions.In certain embodiments, there is provided be incorporated into following The antibody of one or more of Tau fragments or whole：2-24,7-24,7-20,10-24,7-21,8-22 and 11-25.One In a little embodiments, there is provided be incorporated into SEQ ID NO：The peptide of 593 sequence but it is not incorporated into SEQ ID NO：596 Or SEQ ID NO：The antibody of the peptide of 597 sequence.
In another aspect of this invention, it is monoclonal antibody according to the anti-Tau antibody of any the embodiment above, including it is embedding Close antibody, humanized antibody or human antibody.In one embodiment, anti-Tau antibody is antibody fragment, such as Fv, Fab, Fab ', scFv, double-chain antibody or F (ab ')2Fragment.In another embodiment, antibody is full length antibody, such as completely IgG1 or IgG4 antibody or as herein defined other antibody isotypes or homotype.
On the other hand, can be merged as to be retouched in lower part 1 to 7 according to the anti-Tau antibody of any the embodiment above Any one in single or combination the feature stated.
1. affinity of antibody
In certain embodiments, the dissociation constant (K of antibody provided in this articleD) for≤1 μM ,≤100nM ,≤ 10nM ,≤1nM ,≤0.1nM ,≤0.01nM or≤0.001nM (such as 10-8M or 10-8Below M, such as 10-8M to 10-13M, example Such as 10-9M to 10-13M)。
In some embodiments, K is measured by radiolabeled antigen binding measure (RIA)D.In some embodiment party In case, RIA is carried out with the target antibody and its antigen of Fab patterns.For example, Fab leads to the solution binding affinity of antigen Measured below crossing：Make in the presence of the titration series of unlabelled antigen Fab and least concentration (125I) labelled antigen balances, Then caught with the culture plate coated through anti-Fab antibody and combine antigen (see, for example, Chen et al., J.Mol.Biol.293： 865-881(1999))., will in order to establish condition determinationPorous culture plate (Thermo Scientific) stayed overnight with 50mM sodium carbonate (pH 9.6) coating that anti-Fab antibody (Cappel Labs) is caught containing 5 μ g/ml, And then the PBS containing 2% (w/v) bovine serum albumin(BSA) is used to close two hours to five hours under room temperature (about 23 DEG C).In nothing In adsorbent culture plate (Nunc#269620), by 100pM or 26pM [125I] antigen and target Fab (such as meet anti-vegf and resist Body Fab-12 assessment, Presta et al., Cancer Res.57：4593-4599 (1997)) serial dilution mixing.Then Target Fab is cultivated to stay overnight；However, sustainable longer period (such as 65 hours) is cultivated to ensure to reach balance.Hereafter, in room Mixture is transferred under temperature and caught in culture plate for cultivation (such as continuing one hour).Solution is then removed, and will training Support disk and use and contain 0.1% polysorbate20PBS eight times.When culture plate is dried, addition 150 Scintillator (the MICROSCINT-20 in μ l/ holesTM；Packard), and in TOPCOUNTTMTo culture on gamma counter (Packard) Disc gage number 10min.The concentration that selection provides each Fab less than or equal to 20% maximum combined is used for competitive binding assay.
According to another embodiment, useSurface plasma resonance is determined to measure KD.Citing comes Say, use- 2000 or- 3000 (BIAcore, Inc., Piscataway, NJ), at 25 DEG C It is lower to be measured with immobilized antigen CM5 chips with about 10 resonance units (RU).In some embodiments, saying according to supplier Bright book, with N- ethyls-N '-(3- dimethylamino-propyls)-carbodiimide hydrochloride (EDC) and N- hydroxysuccinimides (NHS) carry out activated carboxyl to methylate dextran biosensor chip (CM5, BIACORE, Inc.).With 10mM sodium acetates (pH 4.8) by antigen diluent to 5 μ g/ml (about 0.2 μM), then injected with 5 μ l/min flow velocity to obtain about 10 resonance units (RU) coupling protein.After injections of antigens, 1M monoethanolamines are injected to block unreacted radical.For kinetic measurement, At 25 DEG C, Fab is injected in containing 0.05% polysorbate20 (TWEEN-20 with about 25 μ l/min flow velocityTM) interfacial activity Twice of serial dilution (0.78nM to 500nM) in the PBS (PBST) of agent.Use simple one-to-one Lang Gemiaoer combinations mould Type (Langmuir binding model) (Assess software 3.2 editions), felt by being fitted association and dissociation simultaneously Mapping calculates association rate (kon) and dissociation rate (koff).Equilibrium dissociation constant (KD) with ratio koff/konTo calculate.Referring to For example, Chen et al., J.Mol.Biol.293：865-881(1999).If determined by above-mentioned surface plasmon resonance assay Association rate more than 106M-1s-1, then association rate can determine that the technology is in such as spectrometer by using fluorescent quenching technology (fluid stopping equipment type light splitting luminance meter (Aviv Instruments) or 8000- series SLM- such as with stirring-type light analysis groove AMINCOTMLight splitting luminance meter (ThermoSpectronic)) in the presence of the measured increased antigen of concentration, surveyed at 25 DEG C PBS (pH 7.2) of the amount containing the anti-antigen-antibodies of 20nM (Fab forms) fluorescent emission intensity (excites=295nm；Transmitting= 340nm, 16nm band logical) increase or decrease.
2. antibody fragment
In certain embodiments, antibody provided in this article is antibody fragment.Antibody fragment includes but is not limited to Fab、Fab′、Fab′-SH、F(ab′)2, Fv and scFv fragments, and other fragments described below.On some antibody fragments Summary, referring to Hudson et al., Nat.Med.9：129-134(2003).On the summary of scFv fragments, see, for example, Pluckth ü n, The Pharmacology of Monoclonal Antibodies, volume 113, Rosenburg and Moore Compile, (Springer-Verlag, New York), the 269-315 pages (1994)；It see also WO 93/16185；And United States Patent (USP) No. 5,571,894 and No. 5,587,458.On comprising relief receptor binding domain residue and with half-life period inside extending Fab and F (ab ')2The discussion of fragment, referring to U.S. Patent No. 5,869,046.
Double-chain antibody is the antibody fragment with two antigen binding sites, and it can be divalence or bispecific antibody piece Section.See, for example, EP 404,097；WO 1993/01161；Hudson et al., Nat.Med.9：129-134(2003)；With Hollinger et al., Proc.Natl.Acad.Sci.USA 90：6444-6448(1993).Three chain antibodies and four chain antibodies are also It is described in Hudson et al., Nat.Med.9：In 129-134 (2003).
Single domain antibody is that the heavy chain variable domain comprising antibody all or part of or light-chain variable domain is all or part of Antibody fragment.In certain embodiments, single domain antibody behaviour single domain antibody (Domantis, Inc., Waltham, MA；Referring to Such as U.S. Patent No. 6,248,516 B1).
Antibody fragment can be made by various technologies, including but not limited to proteolytic digestion complete antibody and be passed through Recombinant host cell (such as Escherichia coli (E.coli) or bacteriophage) produces, as described herein.
3. chimeric and humanized antibody
In certain embodiments, antibody provided in this article is chimeric antibody.Some chimeric antibodies are described in for example beautiful State's patent the 4,816,567th；With Morrison et al., Proc.Natl.Acad.Sci.USA, 81：6851-6855(1984)) In.In one embodiment, chimeric antibody includes non-human variable domains (for example, deriving from mouse, rat, hamster, rabbit or inhuman spirit The variable region of long class animal (such as monkey)) and human constant region.In another embodiment, chimeric antibody is anti-for " class switch " Body, wherein classification or subclass change from the classification or subclass of parental antibody.Chimeric antibody includes its antigen-binding fragment.
In certain embodiments, chimeric antibody is humanized antibody.Generally, humanization is carried out to non-human antibody to reduce To the immunogenicity of people, while retain the specificity and affinity of parent non-human antibody.In general, humanized antibody includes one Individual or multiple variable domains, wherein HVR, such as CDR (or part thereof) derive from non-human antibody, and FR (or part thereof) derive from people Antibody sequence.Humanized antibody optionally also includes at least a portion of human constant regions.In some embodiments, humanization Some FR residues in antibody pass through the corresponding residue from non-human antibody's (for example, antibody in HVR residues institute source) and substituted with example As recovered or improving antibody specificity or affinity.
Humanized antibody and its manufacture method are summarized in such as Almagro and Fransson, Front.Biosci.13： In 1619-1633 (2008), and it is further described in such as Riechmann et al., Nature 332：323-329(1988)； Queen et al., Proc.Nat ' l Acad.Sci.USA 86：10029-10033(1989)；U.S. Patent No. 5,821,337, No. 7,527,791, No. 6,982,321 and No. 7,087,409；Kashmiri et al., Methods 36：25-34 (2005) (description specificity determines area (SDR) transplanting)；Padlan, Mol.Immunol.28：489-498 (1991) (description " tables Mould again in face ")；Dall ' Acqua et al., Methods 36：43-60 (2005) (description " FR reorganization ")；With Osbourn et al., Methods 36：61-68 (2005) and Klimka et al., Br.J.Cancer, 83：252-260 (2000) be (description FR reorganization " guiding selection " method) in.
People's framework region available for humanization includes but is not limited to：What " best fit (the best-fit) " method of use selected Framework region is (see, for example, Sims et al., J.Immunol.151：2296(1993))；From with light chain or weight chain variable district The consensus of the human antibody of specific subgroup framework region (see, for example, Carter et al., Proc.Natl.Acad.Sci.USA, 89：4285(1992)；With Presta et al., J.Immunol., 151：2623(1993))；People's maturation (somatic mutation) framework Area or people's system genitale framework region are (see, for example, Almagro and Fransson, Front.Biosci.13：1619-1633 (2008))；With the framework region from screening FR libraries (see, for example, Baca et al., J.Biol.Chem.272：10678- 10684 (1997) and Rosok et al., J.Biol.Chem.271：22611-22618(1996)).
4. human antibody
In certain embodiments, antibody provided in this article is human antibody.Various skills as known in the art can be used Art produces human antibody.Human antibody general description is in van Dijk and van de Winkel, Curr.Opin.Pharmacol.5： 368-74 (2001) and Lonberg, Curr.Opin.Immunol.20：In 450-459 (2008).
Human antibody can be by reacting on antigen attack to produce complete human antibody or have people variable region to having modified The transgenic animals of complete antibody apply immunogene and prepare.Such animal usually contains the complete of human immunoglobulin gene's seat Portion or a part, it replaces endogenous immunoglobulin genes seat, or is present in that chromosome is outer or random integration to animal is dyed In body.In such transgenic mice, endogenous immunoglobulin genes seat has typically inactivated.On being obtained from transgenic animals The summary of the method for human antibody, referring to Lonberg, Nat.Biotech.23：1117-1125(2005).It see also and for example describe XENOMOUSETMThe U.S. Patent No. of technology No. 6,075,181 and No. 6,150,584；DescriptionU.S. of technology State's patent the 5,770,429th；K-M is describedThe U.S. Patent No. of technology 7,041,870；And descriptionThe Patent Application Publication of technology the US2007/0061900th.Produced by this class animal The people variable region of complete antibody can further be modified, such as by being combined with different human constant regions.
Human antibody can be also made by the method based on hybridoma.People's marrow for producing human monoclonal antibodies has been described Knurl and the miscellaneous myeloma cell strain of mouse-people.(see, for example, Kozbor J.Immunol., 133：3001(1984)；Brodeur etc. People, Monoclonal Antibody Production Techniques and Applications, the 51-63 pages (Marcel Dekker, Inc., New York, 1987)；With Boemer et al., J.Immunol., 147：86(1991).) via Human antibody is also described in Li et al., Proc.Natl.Acad.Sci.USA, 103 caused by human B-lymphocyte hybridoma technology：3557- In 3562 (2006).Other method includes such as U.S. Patent No. 7,189,826 and (describes to produce Dan Ke from hybridoma cell strain Grand human IgM antibody) and Ni, Xiandai Mianyixue, 26 (4)：Retouched in 265-268 (2006) (description people-people's hybridoma) Those methods stated.People's hybridoma technology (three-source hybridoma technology (Trioma technology)) is also described in Vollmers And Brandlein, Histology and Histopathology, 20 (3)：927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27 (3)：In 185-91 (2005).
Human antibody can also be sheerly variable domain sequence generation by separating the Fv selected from people source phage display library.It is such can Domain sequence can be combined then with required people's constant domain.It is described below for the technology from antibody library selection human antibody.
5. library source antibody
The antibody of the present invention can be by separating for the antibody screening combinatorial libraries with required one or more activity. For example, a variety of methods are used to produce phage display library and for anti-with required binding characteristic as is generally known in the art Body screens such library.Such method survey is in such as Hoogenboom et al. Methods in Molecular Biology 178：In 1-37 (O ' Brien et al. are compiled, Human Press, Totowa, NJ, 2001), and it is further described in for example McCafferty et al., Nature 348：552-554；Clackson et al., Nature 352：624-628(1991)；Marks Et al., J.Mol.Biol.222：581-597(1992)；Marks and Bradbury, Methods in Molecular Biology 248：161-175 (Lo is compiled, Human Press, Totowa, NJ, 2003)；Sidhu et al., J.Mol.Biol.338 (2)：299-310(2004)；Lee et al., J.Mol.Biol.340 (5)：1073-1093(2004)；Fellouse, Proc.Natl.Acad.Sci.USA 101(34)：12467-12472(2004)；With Lee et al., J.Immunol.Methods 284(1-2)：In 119-132 (2004).
In some bacteriophages methods of exhibiting, the pedigree of VH and VL genes is cloned by polymerase chain reaction (PCR) respectively And recombinated at random in phage library, then can be such as Winter et al., Ann.Rev.Immunol.12：433-455(1994) Described in, screened for antigen binding bacteriophage.Bacteriophage is generally with scFv (scFv) fragment or Fab pieces Antibody fragment is presented.Library from immune origin provides the former high-affinity antibody of anti-immunity without building hybridoma.Or Person, original pedigree (such as from people) can be cloned to provide for the single of various non-self-antigen and self-antigen Antibody sources are without any immunity inoculation, such as Griffiths et al., EMBOJ, 12：725-734 (1993) is described.Finally, Primary libraries can be with synthesis mode by from the not rearranged V constant gene segment Cs of stem cell clone, and use contains random sequence With code level variable C DR3 areas and the PCR primer reset in vitro is realized to be made, such as by Hoogenboom and Winter, J.Mol.Biol., 227：381-388 (1992) is described.Describing the patent publication of human antibody phage library is included for example： U.S. Patent No. 5,750,373 and U.S. Patent Publication case the 2005/0079574th, No. 2005/0119455, the No. 2005/0266000, No. 2007/0117126, No. 2007/0160598, No. 2007/0237764, the 2007/th No. 0292936 and No. 2009/0002360.
It is considered as human antibody or human antibody fragment herein from the antibody or antibody fragment of the separation of human antibody library.
6. multi-specificity antibody
In certain embodiments, antibody provided in this article is multi-specificity antibody, such as bispecific antibody.It is more special Heterogenetic antibody is the monoclonal antibody for having at least two different locis binding specificity.In certain embodiments, with reference to It for Tau and another one is to be directed to any other antigen that one of specificity, which is,.In certain embodiments, binding specificity One of be for Tau and another one be to be directed to amyloid beta.In certain embodiments, bispecific antibody can be tied Together in Tau two different epitopes.Bispecific antibody can also be used to make cytotoxic agent be positioned on expression Tau cell. Bispecific antibody can be prepared with full length antibody or antibody fragment format.
Technology for manufacturing multi-specificity antibody, which includes but is not limited to recombinant co-expression, has difference specific two Individual heavy chain immunoglobulin-light chain is to (referring to Milstein and Cuello, Nature 305：537 (1983)), WO 93/ 08829, and Traunecker et al., EMBO are J.10：3655 (1991)), and " pestle-mortar (knob-in-hole) " engineered (see, for example, U.S. Patent No. 5,731,168).Multi-specificity antibody can be also manufactured by the following：For prepare antibody Fc- The engineering electrostatic guide effect (WO 2009/089004A1) of heterodimeric molecule；Hand over two or more antibody or fragment Connection (see, for example, U.S. Patent No. 4,676,980 and Brennan et al., Science, 229：81(1985))；Use bright ammonia Sour slide fastener produces bispecific antibody (see, for example, Kostelny et al., J.Immunol., 148 (5)：1547-1553 (1992))；Using for manufacturing bispecific antibody fragment " double-chain antibody " technology (see, for example, Hollinger et al., Proc.Natl.Acad.Sci.USA, 90：6444-6448(1993))；With using scFv (sFv) dimer (see, for example, Gruber et al., J.Immunol., 152：5368(1994))；With such as such as Tutt et al., J.Immunol.147：60(1991) Described in prepare three-specific antibody.
Also include the engineered antibody with three or three function above antigen binding sites, bag herein Include " octopus antibody (Octopus antibodies) " (see, for example, US 2006/0025576A1).
This paper antibody or fragment is also including " economic benefits and social benefits FAb " or " DAF ", it, which is included, is incorporated into Tau and another difference The antigen binding site of antigen (see, for example, US 2008/0069820).
7. antibody variants
In certain embodiments, the amino acid sequence variation of antibody provided in this article is covered.For example, Ke Nengxu Improve the binding affinity and/or other biological property of antibody.The amino acid sequence variation of antibody can be by will suitably modify It is introduced in the nucleotide sequence of encoding said antibody or is prepared by peptide symthesis.Such modification is included for example in the ammonia of antibody The missing of residue in base acid sequence and/or insertion and/or substitution.Any combinations that can be lacked, inserted and be substituted are to obtain Final construct is obtained, its restrictive condition is that final construct has required feature, such as antigen binding.
a)Substitution, insertion and deletion mutants
In certain embodiments, there is provided there are the antibody variants of one or more 49-Phe ,82-Ser,115-Arg,144-Met,145-Asn ,161-Arg,169-Met Human Connective tissue growth factors.Lured for substituted type The target site of change includes HVR and FR.Conservative replaces are showed in table 1 under " preferably substituting " title.More substantial variation carries For under title in table 1 " exemplary substitution ", and further described below with reference to amino acid side chain classification.Amino acid can be taken In generation, is introduced in target antibody, and for following required screening active ingredients product：Such as reservation/improvement antigen binding, reduce Immunogenicity or the ADCC or CDC of improvement.
Table 1
Amino acid can be grouped according to shared side chain properties：
(1) hydrophobicity：Nor-leucine, Met, Ala, Val, Leu, Ile；
(2) Neutral hydrophilic：Cys、Ser、Thr、Asn、Gln；
(3) it is acid：Asp、Glu；
(4) it is alkaline：His、Lys、Arg；
(5) residue of chain orientation is influenceed：Gly、Pro；
(6) aromatics：Trp、Tyr、Phe.
Non-conservation substitution changes certainty into another category with by the member of one of these classifications.
A type of substituted type variant be related to substitution parental antibody one of (such as humanized antibody or human antibody) or Multiple some hypervariable region residues.In general, the gained variant for being selected to further study will be in some biologies relative to parental antibody Properties have modification (such as improvement) (such as affinity improves, immunogenicity reduces) and/or will substantially retain parent Some biological properties of antibody.A kind of exemplary substituted type variant is affinity maturation antibody, and it can be for example using based on phagocytosis The affinity maturation technology (all those technologies as described herein) of body display advantageously produces.In simple terms, make one or Multiple HVR residue mutations, and antibody variants are presented on bacteriophage and enter for particular organisms active (such as binding affinity) Row screening.
Changing (such as substitution) can be carried out for example to improve affinity of antibody in HVR.Such change can be at HVR " focus " (i.e. as during body cell maturation undergo high-frequency be mutated codon coded by residue (see, for example, Chowdhury, Methods Mol.Biol.207：179-196 (2008)), and/or contact antigen residue) in carry out, wherein Test gained variant VH or VL binding affinity.By building two level library and reaching affinity from two level library reselection Maturation has been described in Hoogenboom et al. Methods in Molecular Biology 178：1-37 (O ' Brien et al. Compile, Human Press, Totowa, NJ, (2001)).In some embodiments of affinity maturation, pass through a variety of method (examples Such as the mutagenesis that fallibility PCR, chain reorganization or oligonucleotides guide) any one of diversity is introduced to it is selected be used for maturation can Become in gene.Then produce two level library.The library is then screened to differentiate any antibody variants with required affinity.Separately One kind introduces multifarious method and is related to HVR bootstrap techniques, wherein some HVR residues (for example, a 4-6 residue) are random Packet.The HVR residues involved by antigen binding can specifically be differentiated, such as reflected using alanine scanning mutagenesis or modelling Not.In particular, CDR-H3 and CDR-L3 is usually targetted.
In certain embodiments, substituting, insert or lacking can occur in one or more HVR, as long as such change The ability of not essentially decreased antibodies bind antigen.For example, not essentially decreased combination can be carried out in HVR affine The conservative of power sexually revises (for example, conservative replaces as herein provided).Such change can contact antigen for example in HVR The outside of residue.In some embodiments of variant VH and VL sequence presented above, each HVR does not change or containing not surpassing Cross one, two or three 49-Phe ,82-Ser,115-Arg,144-Met,145-Asn ,161-Arg,169-Met Human Connective tissue growth factor.
A kind of method in antibody residue that can be targetted suitable for discriminating mutagenesis or area is referred to as " alanine scanning mutagenesis ", such as Cunningham and Wells (1989) Science, 244：Described by 1081-1085.In this method, the residual of target residue is differentiated Base or group's (such as charged residues, such as arg, asp, his, lys and glu) and through neutral or negatively charged amino acid (such as the third ammonia Acid or polyalanine) replace to determine whether the interaction of antibody and antigen is impacted.Function can showed to initial substitution Other substitutions are introduced at the amino acid position of sensitiveness.Besides or furthermore, reflected using the crystal structure of antigen-antibody complex Other contact point between antibody and antigen.Such contact residues and neighbouring residue can take as the target of substitution candidate or exclusion Outside candidate.Variant can be screened to determine if the property containing needed for.
Amino acid sequence insertion includes length between a residue to the polypeptide containing 100 or more than 100 residues In the range of aminoterminal and/or c-terminus fusion, and single or multiple amino acid residues sequence in insert.End is inserted Example include with N-terminal first thiamines acyl residue antibody.The N-terminal of other insert type variants of antibody molecule including antibody or C-terminal and the fusion of enzyme (such as ADEPT) or the polypeptide for the serum half-life for extending antibody.
b)Glycosylation variants
In certain embodiments, antibody provided in this article is changed to increase or decrease the journey of antibody glycosylation Degree.Glycosylation site is added into antibody or make antibody missing glycosylation site can by changing amino acid sequence to produce or One or more glycosylation sites are removed advantageously to realize.
In the case where antibody includes Fc areas, the carbohydrate of attachment thereon can be changed.Produced by mammalian cell Raw primary antibody generally comprises the double antennary oligosaccharides of branched chain, and it typically attaches to the Asn297 in the CH2 domains in Fc areas by N keys On.See, for example, Wright et al. TIBTECH 15：26-32(1997).Oligosaccharides may include various carbohydrate, such as sweet dew Sugar, N- acetyl glucosamines (GlcNAc), galactolipin and sialic acid, and attach in " trunk " of double antennary oligosaccharide structures Trehalose on GlcNAc.In some embodiments, the oligosaccharides in the antibody of the present invention can be modified to produce tool There are the antibody variants of the property of some improvement.
In some embodiments, there is provided have and lack attachment (direct or indirect) in the carbon aquation of the trehalose in Fc areas The antibody variants of compound structure.For example, the amount of the trehalose in this antibody-like can be 1% to 80%, 1% to 65%, 5% To 65% or 20% to 40%.The amount of trehalose is by calculating the trehalose in sugar chain at Asn297 relative to such as passing through MALDI- All sugared structures (such as compound, hybridization and high mannose structures) attached on Asn 297 measured by TOF mass spectrometries The average magnitude of summation determine, as described in such as WO 2008/077546.Asn297 refers to be located at Fc areas Zhong Yue positions Asparagine residue (the Eu numberings of Fc areas residue) at 297；Change however, being attributed to minor sequence in antibody, Asn297 is also It can be located at upstream or about ± 3, the downstream amino acid of position 297, i.e., between position 294 and 300.Such mycose-base The ADCC functions of improvement can be had by changing variant.See, for example, U.S. Patent Publication case US 2003/0157108 (Presta, L.)；US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd).On " de- fucosylated " or " lack The example of the publication of trehalose " antibody variants includes：US 2003/0157108；WO 2000/61739；WO 2001/ 29246；US 2003/0115614；US 2002/0164328；US 2004/0093621；US 2004/0132140；US 2004/0110704；US 2004/0110282；US 2004/0109865；WO 2003/085119；WO 2003/084570；WO 2005/035586；WO 2005/035778；WO2005/053742；WO2002/031140；Okazaki et al. J.Mol.Biol.336：1239-1249(2004)；Yamane-Ohnuki et al. Biotech.Bioeng.87：614(2004). The example of the cell line of de- fucosylated antibody, which can be produced, to be included lacking the fucosylated Lec13 Chinese hamster ovary celIs of protein (Ripka et al., Arch.Biochem.Biophys.249：533-545(1986)；U.S. Patent Application No. US 2003/ 0157108 No. A1, Presta, L；With WO 2004/056312 A1, Adams et al., especially embodiment 11), and gene knockout Cell line, such as α -1,6- fucosyltransferases gene (FUT8) gene knockout Chinese hamster ovary celI is (see, for example, Yamane- Ohnuki et al., Biotech.Bioeng.87：614(2004)；Kanda, Y. et al., Biotechnol.Bioeng., 94 (4)： 680-688(2006)；And WO2003/085107).
Antibody variants, which further have, is cut into two parts of oligosaccharides, such as the double antennary oligosaccharides wherein attached in the Fc areas of antibody Two parts are cut into by GlcNAc.Such antibody variants can have fucosylated and/or improvement the ADCC functions of reducing.It is such The example of antibody variants is described in such as WO 2003/011878 (Jean-Mairet et al.)；U.S. Patent No. 6,602,684 (Umana et al.)；With US 2005/0123546 (Umana et al.).At least one galactose residue additionally provided in oligosaccharides is attached The antibody variants being connected in Fc areas.Such antibody variants can have the CDC functions of improvement.Such antibody variants are described in such as WO 1997/30087 (Patel et al.)；WO 1998/58964 (Raju, S.)；In WO 1999/22764 (Raju, S.).
c)Fc region variants
In certain embodiments, can be by one or more amino acid modified Fc areas for being introduced to antibody provided in this article In, so as to produce Fc region variants.Fc region variants can include people Fc region sequences (such as human IgG1, IgG2, IgG3 or IgG4 Fc Area), it is included amino acid modified (such as substitution) in one or more amino acid positions.
In certain embodiments, the present invention covers with some and the antibody variants of not all effector function, and this causes The antibody turns into most important for wherein internal antibody half-life period, and some effector functions (such as complement and ADCC) is not The necessary or harmful desirable candidate of application.External and/or in vivo cytotoxicity measure can be carried out with confirm CDC and/ Or reduction/consumption of ADCC activity.For example, Fc acceptors (FcR) combination mensuration can be carried out to ensure that antibody deficiency Fc γ R are tied Close (therefore ADCC activity may be lacked), but retain FcRn binding abilities.For mediating ADCC primary cell NK cells only table Up to Fc γ RIII, and monocytes Fc γ RI, Fc γ RII and Fc γ RIII.Expression of the FcR on hematopoietic cell is summarized in Ravetch and Kinet, Annu.Rev.Immunol.9：In 457-492 (1991) table 3 of page 464.To assess target The non-limiting examples of the external test of the ADCC activity of molecule be described in U.S. Patent No. 5,500,362 (see, for example, Hellstrom, I. et al. Proc.Nat ' l Acad.Sci.USA 83：7059-7063 (1986)) and Hellstrom, I et al., Proc.Nat′l Acad.Sci.USA 82：1499-1502(1985)；5th, 821, No. 337 (referring to Bruggemann, M. etc. People, J.Exp.Med.166：1351-1361 (1987)) in.Or on-radiation assay method can be used (see, for example, flowing The ACTI of formula cell measurement artTMNon-radioactive cell toxicity test (CellTechnology, Inc.Mountain View, CA)； And CytoToxNon-radioactive cell toxicity test (Promega, Madison, WI)).It is thin suitable for the effect of such measure Born of the same parents include peripheral blood monocytes (PBMC) and natural killer (NK) cell.Besides or furthermore, target molecule can be assessed in vivo ADCC activity, such as in animal model, such as Clynes et al. Proc.Nat ' l Acad.Sci.USA 95：652-656 (1998) animal model disclosed in.C1q combination mensurations can also be carried out and C1q and therefore lacked with confirming that antibody can not combine CDC activity.See, for example, C1q the and C3c combinations ELISA in WO 2006/029879 and WO 2005/100402.In order to assess Complement activation, CDC measure can be carried out (see, for example, Gazzano-Santoro et al., J.Immunol.Methods 202：163 (1996)；Cragg, M.S. et al., Blood 101：1045-1052(2003)；And Cragg, M.S. and M.J.Glennie, Blood 103：2738-2743(2004)).Method as known in the art also can be used (see, for example, Petkova, S.B. etc. People, Int ' l.Immunol.18 (12)：1759-1769 (2006)) progress FcRn is combined and internal clearance rate/half-life period measure.
The antibody that effector function reduces is included with one in Fc areas residue 238,265,269,270,297,327 and 329 Person or those substituted antibody (U.S. Patent No. 6,737,056) of more persons.Such Fc mutant includes having amino acid position Substituted Fc mutant more than both in 265,269,270,297 and 327 or both is put, including residue 265 and 297 substitutes For so-called " DANA " the Fc mutant (U.S. Patent No. 7,332,581) of alanine.
Description has some antibody variants of combination improve or weaken and FcR.(see, for example, U.S. Patent No. 6, No. 737,056；WO 2004/056312 and Shields et al., J.Biol.Chem.9 (2)：6591-6604(2001)).
In certain embodiments, antibody variants include the 49-Phe ,82-Ser,115-Arg,144-Met,145-Asn ,161-Arg,169-Met Human Connective tissue growth factor with one or more improvement ADCC, such as The substituted Fc areas of (the EU numberings of residue) at the position 298,333 and/or 334 in Fc areas.
In some embodiments, it is changed in Fc areas, causes C1q combinations and/or complement-dependent cytotoxicity (CDC) change and (improve or weaken), for example, such as U.S. Patent No. 6,194,551, WO 99/51642 and Idusogie etc. People J.Immunol.164：Described in 4178-4184 (2000).
Increased Plasma Half-life and be responsible for by Maternal immunoglobulin G be transferred to fetus neonatal Fc receptor (FcRn) (Guyer et al., J.Immunol.117：587 (1976) and Kim et al., J.Immunol.24：249 (1994)) combination improvement antibody description In US2005/0014934A1 (Hinton et al.).Those antibody include the Fc areas wherein with one or more substitutions, institute State substitution improvement Fc areas and FcRn combination.Such Fc variants be included in one or more of following Fc areas residue place have take Those variants in generation：238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、 378th, 380,382,413,424 or 434, such as the substitution (U.S. Patent No. 7,371,826) of Fc areas residue 434.
On other examples of Fc region variants, Duncan and Winter, Nature 322 see also：738-40(1988)； U.S. Patent No. 5,648,260；U.S. Patent No. 5,624,821；With WO 94/29351.
d)Through the engineered antibody variants of cysteine
In some embodiments it may be necessary to produce through the engineered antibody of cysteine, such as " thioMAb ", One or more residues of wherein antibody substitute through cysteine residues.In specific embodiments, the residue being substituted is present At the reachable site of antibody.Substitute those residues by using cysteine, reactive mercapto can so as to be positioned at antibody At up to site and it can be used for making antibody combine with other parts (such as drug moiety or linker-drug part) to produce as herein In the immunoconjugates that further describe.In certain embodiments, any one of following residue or more persons can be through half Guang ammonia Acid substitution：The V205 (Kabat numberings) of light chain；The A118 (EU numberings) of heavy chain；With the S400 (EU numberings) in heavy chain Fc areas.Can be such as Such as produced described in U.S. Patent No. 7,521,541 through the engineered antibody of cysteine.
e)Antibody derivatives
In certain embodiments, antibody presented herein can be carried out further modification with containing in this area Know and readily available extra non-protein portion.The part for being suitable for antibody derivatization includes but is not limited to water solubility Polymer.It is common that the non-limiting examples of water-soluble polymer include but is not limited to polyethylene glycol (PEG), ethylene glycol/propylene glycol Polymers, carboxymethyl cellulose, glucan, polyvinyl alcohol, polyvinylpyrrolidone, poly- 1,3- dioxolane, poly- 1,3, 6- trioxanes, ethene/maleic anhydride multipolymer, polychlorostyrene base sour (homopolymer or random copolymer) and glucan or Poly- (n-VP) polyethylene glycol, polypropylene glycol homopolymer, PPOX/ethylene oxide copolymer, polyoxyethylene Polyalcohol (for example, glycerine), polyvinyl alcohol and its mixture.Methoxy PEG-propionaldehyde can manufacture because of its stability in water In there is advantage.Polymer can have any molecular weight, and can be branch or non-branch.The polymer attached on antibody Number alterable, and if being attached more than one polymer, then it can be identical or different molecule.In general, for deriving The number and/or type of the polymer of effect can be resisted based on the special nature or function of including but not limited to antibody to be improved Whether syntaxy thing will be determined for Considerations such as the therapies under specified requirements.
In another embodiment, there is provided antibody with can be by the non-protein that is selectively heated in radiation The conjugate of matter part.In some embodiments, non-protein portion be CNT (Kam et al., Proc.Natl.Acad.Sci.USA 102：11600-11605(2005)).Any wavelength can be had by radiating, and including (but not It is limited to) ordinary cells are not damaged but non-protein portion is heated to killing to the temperature of the cell of antibody-non-protein portion nearside The wavelength of degree.
B. recombination method and composition
It can be used for example such as the recombination method and composition generation antibody described in U.S. Patent No. 4,816,567. In some embodiments, there is provided a kind of separated nucleic acid for encoding anti-Tau antibody described herein.Such nucleic acid can be compiled VL of the code comprising antibody amino acid sequence and/or VH comprising antibody amino acid sequence (such as the light chain of antibody and/or again Chain).In another embodiment, there is provided one or more include the carrier (such as expression vector) of such nucleic acid.Another In individual embodiment, there is provided include the host cell of such nucleic acid.In such embodiment, host cell includes (example Converted as following)：(1) core comprising amino acid sequence of the coding comprising antibody VL and the amino acid sequence comprising antibody VH The carrier of acid；Or (2) include the first vector of the nucleic acid of amino acid sequence of the coding comprising antibody VL and comprising coding comprising anti- The Second support of the nucleic acid of body VH amino acid sequence.In some embodiments, host cell is eukaryotic, such as China Hamster Qvary (CHO) cell or lymphocyte (such as Y0, NS0, Sp20 cell).In some embodiments, there is provided one kind system The method for making anti-Tau antibody, wherein methods described, which are included in, to be suitable for cultivating confession as mentioned above under conditions of expression antibody The host cell of nucleic acid comprising encoding said antibody, and optionally reclaimed from the host cell (or host cell culture medium) The antibody.
Restructuring for anti-Tau antibody produces, and separation encodes the nucleic acid of antibody for example as described above, and is inserted Enter into one or more carriers for further cloning and/or expressing in host cell.Such nucleic acid can easily be used Conventional program by using the oligonucleotides for the gene that can be specifically incorporated into encoding antibody heavy and light chain (for example, visited Pin) separate and be sequenced.
The host cell of carrier for being suitable for cloning or expressing encoding antibody includes protokaryon described herein or eucaryon Cell.For example, antibody can produce in bacterium, especially true when that need not glycosylate with Fc effector functions.On anti- The expression of body fragment and polypeptide in bacterium, see, for example, U.S. Patent No. 5,648, No. 237, the 5th, 789, No. 199 and the 5th, No. 840,523.(it see also Charlton, Methods in Molecular Biology, volume 248 (B.K.C.Lo is compiled, Humana Press, Totowa, NJ, 2003), the 245-254 pages, it describes expression of the antibody fragment in Escherichia coli.) After expression, can with soluble fraction from bacterial cell pastel separation antibody and its can be further purified.
In addition to prokaryotes, the eukaryotic microorganisms of such as filamentous fungi or yeast are the carrier for being suitable for encoding antibody Clone or expressive host, including glycosylation pathway is " humanization ", so that caused antibody has partially or completely People glycosylates the fungi and yeasts strain of kenel.Referring to Gerngross, Nat.Biotech.22：1409-1414 (2004) and Li Et al., Nat.Biotech.24：210-215(2006).
The host cell for being suitable for expressing glycosylated antibodies also derives from multicellular organisms (invertebrate and vertebra Animal).The example of invertebral zooblast includes plant and insect cell.Identified it is numerous can combine with insect cell make With the baculoviral strain particularly for transfecting Spodopterafrugiperda (Spodoptera frugiperda) cell.
Plant cell cultures also act as host.See, for example, U.S. Patent No. 5,959,177, the 6,040,498th Number, No. 6,420,548, No. 7,125,978 and No. 6,417,429 (describe to be used to produce antibody in genetically modified plants PLANTIBODIESTMTechnology).
Vertebrate cells also act as host.For example, the mammalian cell strain suitable for being grown in suspension Can be what is be applicable.Other examples for being applicable mammalian host cell strain are the monkey kidney CV1 cells converted through SV40 (COS-7) Strain；Human embryonic kidney cell line is (as example in Graham et al., J.Gen Virol.36：293 described in 59 (1977) or 293 Cell)；Baby hamster kidney cell (BHK)；Mouse Sertoli cell (mouse sertoli cell) (as example in Mather, Biol.Reprod.23：TM4 cells described in 243-251 (1980))；MK cells (CV1)；African green monkey kidney cell (VERO-76)；Human cervical carcinoma cell (HELA)；MDCK (MDCK)；Buffalo rats liver (buffalo rat liver cell)(BRL 3A)；Human pneumonocyte (W138)；Human liver cell (Hep G2)；Mouse mammary tumor (MMT 060562)； As for example in Mather et al., Annals N.Y.Acad.Sci.383：TRI cells described in 44-68 (1982)；MRC 5 Cell；With FS4 cells.Other, which are applicable mammalian host cell strain, includes Chinese hamster ovary (CHO) cell, including DHFR- Chinese hamster ovary celI (Urlaub et al., Proc.Natl.Acad.Sci.USA 77：4216(1980))；And myeloma cell strain, such as Y0, NS0 and Sp2/0.On the summary for some mammalian host cell strains for being suitable for producing antibody, see, for example, Yazaki And Wu, Methods in Molecular Biology, volume 248 (B.K.C.Lo is compiled, Humana Press, Totowa, NJ), The 255-268 pages (2003).
C. determine
Its physical/chemical can be directed to anti-Tau antibody provided in this article by various measure as known in the art Matter and/or bioactivity are differentiated, screened or characterized.
1. combination mensuration and other measure
In one aspect, the antigen-binding activity of the antibody of the present invention is tested, such as by known method, such as ELISA, Immunoblotting etc..
On the other hand, competition assay can be used Tau antibody is incorporated into antibody competition described herein to differentiate. In certain embodiments, it is such competition antibody binding in 94B2-C1,125B11-H3,37D3-H9 or hu37D3- The epitope identical epitope (such as linear or comformational epitope) that H9.v28.A4 is combined.Epitope for being combined to antibody is entered The detailed exemplary methods of row positioning are provided in Morris (1996) " Epitope Mapping Protocols ", in Methods In in Molecular Biology volumes 66 (Humana Press, Totowa, NJ).
In exemplary competition assay, (such as described herein any comprising the first labelled antibody for being incorporated into Tau Antibody, such as hu37D3-H9.v28.A4) and positive test and the first antibody competition binding second do not marked in Tau ability Remember and immobilization Tau (such as monomer Tau) is cultivated in the solution of antibody.Secondary antibody may be present in doma supernatant.As Control, immobilization Tau is cultivated in the solution comprising the first labelled antibody but without the second unmarked antibody.Allowing first antibody It is incorporated into after cultivating under conditions of Tau, removes excessive uncombined antibody, and measure the amount with the mark of immobilization Tau associations. If the amount in test sample with the mark of immobilization Tau associations, relative to being substantially reduced in control sample, it indicates the Two antibody are with first antibody competition binding in Tau.Referring to Harlow and Lane (1988) Antibodies：A Laboratory The chapters of Manual the 14th (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).
2. determination of activity
In one aspect, there is provided for differentiating the measure of anti-Tau (such as general Tau) antibody with bioactivity.Biology Activity may include such as this antibody-like and the Tau of diversified forms (such as monomer Tau, oligomerization Tau, non-phosphorylating Tau and phosphorylation Tau combination) and reduce Tau albumen (for example, in brain, for example, total Tau in Cerebral cortex and/or hippocampus, total soluble T au, can Dissolubility non-phosphorylating Tau, titanium pigment acidifying Tau, total insoluble Tau, insoluble non-phosphorylating Tau, insoluble phosphorylation Tau, peroxophosphoric acid Tau or the conjugate spirals fibril containing peroxophosphoric acid Tau) level.Additionally provide in vivo and/or in vitro Antibody with such bioactivity.
In certain embodiments, such bioactivity of the antibody of the present invention is tested.For example, Protein tau disease Animal model, such as Tau transgenic mices (such as P301L) can be used for the combination for detecting anti-Tau antibody and brain section, and for example And the combination of neurofibrillary tangles in Transgenic Mice Brain.In addition, the animal model of Protein tau disease, such as Tau transgenosis are small Mouse (such as P301L) can use anti-Tau antibody to be handled, and experimental technique is available for such treatment is assessed as is generally known in the art (such as in Cerebral cortex and/or hippocampus) Tau albumen in no reduction mouse brain (such as total Tau, total soluble T au, soluble phosphoric acid Change Tau, soluble non-phosphorylating Tau, total insoluble Tau, insoluble phosphorylation Tau, insoluble non-phosphorylating Tau, peroxophosphoric acid Change Tau or the conjugate spirals fibril containing peroxophosphoric acid Tau) level.
D. immunoconjugates
Present invention also offers the anti-Tau antibody comprising this paper and one or more other therapeutic agents or radio isotope With reference to immunoconjugates.
In another embodiment, immunoconjugates are included and combined with radioactive atom to form radioactivity conjugate Antibody as described herein.A variety of radio isotopes are available for producing radioactivity conjugate.Example includes At211、I131、 I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212With Lu radio isotope.When radioactivity conjugate is used to detect When, it can include the radioactive atom for being used for scintigraphy research, such as tc99m or 1123；Or for nuclear magnetic resonance (NMR) into As the spin labeling of (also referred to as magnetic resonance imaging, mri), and such as iodo- 123, iodine -131, indium -111, fluoro- 19, carbon -13, nitrogen - 15th, oxygen -17, gadolinium, manganese or iron.
It can be used a variety of difunctionality coupled protein agent that the conjugate of antibody is made, the difunctionality coupled protein agent is Such as N- succimides base -3- (2- pyridyidithios) propionic ester (SPDP), succimide base -4- (N- maleics two Imide methyl) hexamethylene -1- formic acid esters (SMCC), iminothiolane (IT), imide ester difunctionality derive Thing (such as diimine is for dimethyl adipate hydrochloride), active ester (such as succimide base ester of suberic acid two), aldehyde are (such as Glutaraldehyde), two-fold nitrilo compound (such as double (to azidobenzoyl) hexamethylene diamines), dual azepine derivatives it is (such as double (to diazoniumbenzoyl)-ethylenediamine), diisocyanate (such as toluene 2,6- diisocyanate) and double activated fluorine compounds (fluoro- 2, the 4- dinitro benzenes of such as 1,5- bis-).For example, ricin immunotoxin can be such as Vitetta et al., Science 238：Prepared described in 1098 (1987).The 1- isothiocyanato benzyl -3- methyl diethylidene three that carbon 14 marks Triamine pentaacetic acid (MX-DTPA) is the exemplary chelating agent for making radioactive nucleotides and antibody binding.Referring to WO94/11026. Joint can be " the cleavable joint " for promoting cytotoxic drug to be discharged in cell.For example, it can be used acid is unstable to connect Head, peptidase-sensitive joint, photo-labile joint, dimethyl linker or joint (Chari et al., Cancer containing disulfide bond Res.52：127-131(1992)；U.S. Patent No. 5,208,020).
This paper immunoconjugates or ADC clearly cover such conjugate of (but not limited to) cross-linking reagent preparation, institute State cross-linking reagent include but is not limited to BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo group-EMCS, sulfo group-GMBS, sulfo group-KMUS, sulfo group-MBS, sulfo group-SIAB, sulfo group-SMCC and sulphur Base-SMPB, and SVSB (succimide base-(4- vinyl sulfones) benzoic ether), the cross-linking reagent it is commercially available (such as Purchased from Pierce Biotechnology, Inc., Rockford, IL., U.S.A).
E. it is used for the method and composition for diagnosing and detecting
In certain embodiments, any one of anti-Tau antibody provided in this article is applied to detection Tau in biological sample Presence in product.Term " detection " as used herein covers quantitative or qualitative detection.In certain embodiments, biological sample Comprising cell or tissue, such as celiolymph, brain cell or tissue (such as Cerebral cortex or hippocampus) or blood.In some embodiment party In case, biological sample is celiolymph.
In some embodiments, there is provided a kind of anti-Tau antibody being used in diagnosis or detection method.On the other hand, A kind of existing methods of detection Tau in biological sample is provided.In certain embodiments, methods described includes making biological sample Product are allowing anti-Tau antibody bindings to be contacted under conditions of Tau with anti-Tau antibody as described herein, and detection is in anti-Tau Whether compound is formed between antibody and Tau.Such method can be external or vivo approaches.Resist in addition, anti-Tau can will be formed in Compound between body and the Tau in test biology sample is with being formed at that to compare biological sample (such as strong from one or more The biological sample of health subject) in compound be compared.Can also be to being formed in anti-Tau antibody and test biology sample The amount of compound between Tau is quantified, and it is compareed into biological sample (such as from one or more health with being formed at The biological sample of subject) in compound amount or carried out with the average magnitude of the known compound being formed in health volunteer Compare.
In some embodiments, select to be suitable to the subject with anti-Tau Antybody therapies using anti-Tau antibody, such as Wherein Tau is the biomarker for patient's selection.For example, in some embodiments, anti-Tau (such as general Tau) Antibody is used to detecting subject whether have Tau albumen disease or an illness, or whether subject is with suffering from Tau albumen disease or disease The excessive risk (or tendency) of disease.
The exemplary disease or illness of the antibody diagnosis of the present invention can be used to include Tau protein related diseases or illness, and Caused or relative disease or illness by being formed for neurofibrillary tangles or neuropil thread.In some embodiments In, can be used the disease of the antibody diagnosis of the present invention or illness be included in cognitive function obstacle or forfeiture in the Tau that shows Protein related diseases or illness, the cognitive function include deduction, situation judgement, memory capability, study and/or special navigation. Specifically, the disease of the antibody diagnosis of the present invention or illness can be used to include Protein tau disease, such as neurodegenerative tau eggs White disease.The exemplary disease or illness of the antibody diagnosis of the present invention can be used to include but is not limited to Alzheimer disease, Ke Ya Er Shi diseases, dementia pugilistica, Down syndrome, lattice, which are applied, thanks San Shi diseases, inclusion body myositis, prion protein brain amyloid blood vessel Disease, traumatic brain injury, amyotrophic lateral sclerosis/guam parkinsonism-dementia complex, with neurofibrillary tangles Non- Guam type motor neuron disease, argyrophilic grain dementia, corticobasal degeneration, the diffusivity neuron with calcification Fibre matting, Frontotemporal dementia, Frontotemporal dementia, the Halle Wo Deng-apply of chain companion's parkinson's syndrome in No. 17 chromosome Pa thatch disease, multiple system atrophy, c-type Niemann-Pick disease, globus pallidus-ponto-nigral degeneration disease, Pick disease, progressive skin Glial cells hyperplasia disease under matter, paralysis on progressive core, subacute sclerosing panencephalitis, only entanglement type is dull-witted, pa gold after encephalitis Gloomy syndrome and myotonia atrophica.In some embodiments, can be used the present invention antibody diagnosis illness for Ah Alzheimer's disease (AD).
In certain embodiments, there is provided the anti-Tau antibody of mark.Mark the mark including but not limited to directly detected Or part (such as fluorescence labeling, chromophore label, electron dense label, chemiluminescent labeling and radioactive label), and example Such as via the part of enzyme reaction or interaction of molecules indirect detection (such as enzyme or part).Exemplary mark includes (but unlimited In) radio isotope32P、14C、125I、3H and131I；Fluorogen, such as Rare Earth Chelate or fluorescein and its derivative；Luo Dan Bright and its derivative；Dansyl；Umbelliferone；Luciferase (luceriferase), such as firefly luciferase and bacterial fluorescence Plain enzyme (U.S. Patent No. 4,737,456)；Fluorescein；2,3- dihydro phthalazine diketones；HRPO (HRP)；Alkaline phosphorus Sour enzyme；Beta galactosidase；Glucoamylase；Lysozyme；Carbohydrate oxidase, for example, glucose oxidase, galactose oxidase and Glucose-6-phosphate dehydrogenase (G6PD)；Heterocyclic oxidases, such as uricase and xanthine oxidase, it using hydrogen peroxide with making dye Expect enzyme (such as HRP, the newborn peroxidase or micro- peroxidase) coupling of precursor oxidation；Biotin/avidin；Spin mark Note；Bacteriophage labels；Stabilized radical and its similar mark.
F. pharmaceutical preparation
The pharmaceutical preparation of anti-Tau antibody as described herein by by this antibody-like with required purity with it is a kind of or The a variety of pharmaceutically acceptable carrier optionally selected, diluent and/or excipient are in the form of lyophilized formulations or the aqueous solution Mix to prepare (Remington ' s Pharmaceutical Sciences the 16th edition, Osol, A. compile (1980)).Pharmaceutically Typically docking receptor is nontoxic under used dosage and concentration for acceptable carrier, diluent and excipient, and including (but not It is limited to)：Sterilized water；Buffer, such as phosphate, citrate and other organic acids；Antioxidant, including ascorbic acid and egg Propylhomoserin；Preservative (such as chlorination octadecyldimethyl benzyl ammonium；Hexamethonium chloride；Benzalkonium chloride；Benzethonium chloride；Benzene Phenol, butanol or phenmethylol；Alkyl paraben, such as methyl p-hydroxybenzoate or propyl ester；Catechol；Isophthalic two Phenol；Cyclohexanol；3- amylalcohols；And metacresol)；Low molecule amount (being less than about 10 residues) polypeptide；The white egg of protein, such as serum In vain, gelatin or immunoglobulin；Hydrophilic polymer, such as polyvinylpyrrolidone；Amino acid, such as glycine, glutamy Amine, asparagine, histidine, arginine or lysine；Monosaccharide and disaccharide and other carbohydrate, including glucose, mannose Or dextrin；Chelating agent, such as EDTA；Sugar, such as sucrose, mannitol, trehalose or D-sorbite；It is all into salt relative ion Such as sodium；Metal composite (such as Zn- protein complexes)；And/or nonionic surface active agent, such as polyethylene glycol (PEG).This paper exemplary pharmaceutically acceptable carrier further comprises interstitial (insterstitial) medicine dispersant, Such as soluble neutral activity sodium hyaluronate enzyme glycoprotein (sHASEGP), such as human soluble PH-20 sodium hyaluronate enzyme glycoprotein, it is all As rHuPH20 (Baxter International, Inc.).Some exemplary sHASEGP (including RHuPH20) it is described in application method in U.S. Patent Publication case No. 2005/0260186 and No. 2006/0104968. On one side, sHASEGP combines with one or more extra glycosaminoglycan enzymes (such as chondroitinase).
Exemplary lyophilized antibodies preparation is described in U.S. Patent No. 6,267,958.Aqueous antibody formulation includes the U.S. Those aqueous antibody formulations described in patent the 6th, 171,586 and WO2006/044908, institute in WO2006/044908 The preparation of description includes histidine-acetate buffer.
This paper preparation active component necessary to the specific adaptations disease treated also containing more than one, it is preferably With will not be to those active components for the complementary activity having a negative impact each other.This active component is compatibly with to expection Purpose is effectively measured combination and existed.
Active component can be wrapped in microcapsules, such as by condensation technique or by micro- prepared by interfacial polymerization Capsule, such as respectively hydroxymethyl cellulose or gelatin-microcapsule and poly- (methyl methacrylate) microcapsules；It is wrapped in glue In state drug delivery system (such as liposome, albumi microspheres, microemulsion, nano-particle and Nano capsule) or thick emulsion In.Such technology is disclosed in Remington ' s Pharmaceutical Sciences the 16th edition, and Osol, A. are compiled in (1980).
Extended release preparation can be prepared.The suitable example of extended release preparation includes the solid hydrophobic polymerization containing antibody The semi-permeable matrix of thing, the matrix are in formed article form, such as film or microcapsules.
Preparation for applying in vivo is generally sterile.Aseptic can be easily for example, by via aseptic filter membrane mistake Filter to realize.
G. Treatment and composition for
Any one of anti-Tau antibody provided in this article can be used in treatment method.
In one aspect, there is provided a kind of anti-Tau antibody, it is used as medicament.In other respects, there is provided a kind of anti-Tau antibody, It is used to treat Tau protein related diseases or illness.In some embodiments, there is provided a kind of anti-Tau antibody, it is used to treat Caused or relative disease or illness by being formed for neurofibrillary tangles or neuropil thread.In particular In, there is provided a kind of anti-Tau antibody, it is used to treat Protein tau disease, such as neurodegenerative Protein tau disease.It can be resisted with anti-tau It is hard that the exemplary Tau protein related diseases or illness of body treatment include but is not limited to Alzheimer disease, amyotrophic lateral Change, Parkinson's, gram refined Er Shi diseases, dementia pugilistica, Down syndrome, lattice are applied and thank San Shi diseases, inclusion body myositis, prion egg White cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/guam parkinsonism-dementia complex, companion Have non-Guam type motor neuron disease of neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, with calcium The Diffuse neurofibrillary entanglement of change, Frontotemporal dementia, the volume temporal lobe of chain companion's parkinson's syndrome in No. 17 chromosome Dementia, Hallervorden Spatz disease, multiple system atrophy, c-type Niemann-Pick disease, globus pallidus-ponto-nigral are degenerated Glial cells hyperplasia disease under disease, Pick disease, progressive cortex, paralysis, subacute sclerosing panencephalitis on progressive core, only tangle Type dementia, postencephalitic parkinsonism and myotonia atrophica.In some embodiments, provided herein is for treating The anti-Tau antibody of Alzheimer disease (AD).In some embodiments, provided herein is for treating moderate AD, slightly into Spend AD, mild AD, early stage AD or preceding drives AD anti-Tau antibody.In addition, it can use the Tau albumen correlation diseases of anti-Tau Antybody therapies Disease or illness be included in cognitive function obstacle or forfeiture in the disease or illness that show, the cognitive function such as infers, Situation judgement, memory capability, study and/or special navigation.In certain embodiments, there is provided a kind of to be used in treatment method Anti- Tau antibody.In certain embodiments, the present invention provides a kind of anti-Tau antibody, and it is used to treat with as described above In the individual method of any of Tau relevant diseases or illness, methods described includes applying effective dose to the individual The anti-Tau antibody.In such embodiment, methods described further comprises applying effective dose extremely to the individual A kind of few additional therapeutic agent for example as described below.
In some embodiments, antibody of the invention be used for treat MMSE scoring between 20 and 30, between 20 with Between 26, between 24 and 30, between 21 and 26, between 22 and 26, between 22 and 28, between 23 and 26 Between, the individual between 24 and 26 or between 25 and 26.In some embodiments, patient MMSE scoring between Between 22 and 26.As used herein, the MMSE scorings between two values include the numerical value at each end points of scope.Citing comes Say, the MMSE scorings between 22 and 26 include 22 and 26 MMSE scorings.
In some embodiments, antibody of the invention is used to treat ' tau the positives ' individual, such as with Tau albumen phases The patient of typical brain tau deposits in related disorders, such as the patient with positive Tau PET scans.
In other embodiments, the present invention provides a kind of anti-Tau antibody, and it is (total that it is used to reduce Tau albumen in individual Tau, total soluble T au, titanium pigment acidifying Tau, total insoluble Tau, insoluble phosphorylation Tau, peroxophosphoric acid Tau contain Peroxophosphoric acid Tau conjugate spirals fibril) level.For example, such a reduction can occur in brain (such as in Cerebral cortex And/or in hippocampus).In some embodiments, the present invention provides a kind of anti-Tau antibody, and it is used for the water for reducing phosphorylation Tau It is flat.In some embodiments, the present invention provides a kind of anti-Tau antibody, and it is used to reducing insoluble Tau (such as can not Soluble phosphorus Be acidified Tau) level.In some embodiments, the present invention provides a kind of anti-Tau antibody, and it is used to reduce peroxophosphoric acid Tau Level.In some embodiments, the present invention provides a kind of anti-Tau antibody, and it is used to reducing in brain tissue (such as Cerebral cortex And/or in hippocampus) level of conjugate spirals fibril (such as conjugate spirals fibril containing peroxophosphoric acid Tau).In some implementations In scheme, the present invention provides a kind of anti-Tau antibody, and it is used to reduce in individual brain (such as in Cerebral cortex and/or hippocampus) Tau eggs In vain (such as total Tau, total soluble T au, titanium pigment acidifying Tau, total insoluble Tau, insoluble phosphorylation Tau, peroxophosphoric acid Tau or the conjugate spirals fibril containing peroxophosphoric acid Tau) horizontal method in, methods described include to it is described individual apply The anti-Tau antibody of effective dose is to reduce the level of Tau albumen." individual " according to any the embodiment above is that lactation is moved Thing, preferably people.
In some embodiments, the present invention provides a kind of anti-Tau antibody, and it is used to adjusting in individual brain (such as brain skin In matter and/or hippocampus) Tau albumen (such as total Tau, total soluble T au, titanium pigment acidifying Tau, total insoluble Tau, can not Soluble phosphorus acidifying Tau, peroxophosphoric acid Tau or the conjugate spirals fibril containing peroxophosphoric acid Tau) level.
On the other hand, the present invention provides the purposes of anti-Tau antibody, and it is used to manufacturing or preparing medicament.In some implementations In scheme, medicament is used to treat Tau protein related diseases or illness.Tau protein related diseases or illness can be by neural fibril Dimension is tangled or the formation of neuropil thread is caused or relative disease or illness.In specific embodiments, medicament is used In treatment Protein tau disease, such as neurodegenerative Protein tau disease.In a particular embodiment, medicament be used for treat be selected from by with The disease or illness of the group of lower composition：Alzheimer disease (AD), gram refined Er Shi diseases, dementia pugilistica, Down syndrome, lattice are applied Thank San Shi diseases, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/ Guam parkinsonism-dementia complex, non-Guam type motor neuron disease with neurofibrillary tangles, Argyophilic grain Dementia, corticobasal degeneration, with the Diffuse neurofibrillary entanglement of calcification, Frontotemporal dementia, it is chain in No. 17 dye The Frontotemporal dementia of companion's parkinson's syndrome of colour solid, Hallervorden Spatz disease, multiple system atrophy, c-type Niemann- Glial cells hyperplasia disease under Pick disease, globus pallidus-ponto-nigral degeneration disease, Pick disease, progressive cortex, fiber crops on progressive core Numbness, only subacute sclerosing panencephalitis, entanglement type dementia, postencephalitic parkinsonism and myotonia atrophica.One In a little embodiments, medicament is used to treat AD.In specific embodiments, medicament is used to treat the obstacle in cognitive function or funeral The Tau relevant diseases or illness that disalignment is shown, the cognitive function is such as inferred, situation judgement, memory capability, study or spy Different navigation.In another embodiment, medicament be used for treat one of disease listed above (such as Protein tau disease, such as AD in method), methods described includes applying the medicament of effective dose to the individual with such disease.In such reality Apply in scheme, at least one that methods described further comprises applying effective dose to individual is for example additionally controlled as described below Treat agent.
In another embodiment, it is (such as total Tau, total soluble T au, soluble non-to be used to reducing Tau albumen for medicament Phosphorylation Tau, titanium pigment acidifying Tau, total insoluble Tau, insoluble phosphorylation Tau, excessively insoluble non-phosphorylating Tau, phosphorus Be acidified Tau or the conjugate spirals fibril containing peroxophosphoric acid Tau) level.For example, such a reduction of Tau albumen can be Observed in the brain of individual in (such as in Cerebral cortex and/or hippocampus) or celiolymph.In some embodiments, medicament is used for Reduce the level of conjugate spirals fibril.In another embodiment, medicament is used to reducing Tau albumen in individual (such as total Tau, total soluble T au, titanium pigment acidifying Tau, total insoluble Tau, insoluble phosphorylation Tau, peroxophosphoric acid Tau contain Peroxophosphoric acid Tau conjugate spirals fibril) horizontal method in, methods described include to it is described individual apply effective dose institute Medicament is stated to reduce the level of Tau albumen." individual " according to any the embodiment above is mammal, preferably people.
On the other hand, the present invention provides a kind of method for treating Tau protein related diseases or illness.Can be according to this The Tau protein related diseases or illness for the method treatment that text is provided are included by neurofibrillary tangles or neuropil thread Formation is caused or relative disease or illness.In specific embodiments, the present invention provides a kind of for treating Protein tau The method of disease, such as neurodegenerative Protein tau disease.In a particular embodiment, the present invention provides one kind and is selected from for treatment The disease of the group consisted of or the method for illness：Alzheimer disease, gram refined Er Shi diseases, dementia pugilistica, Tang Shi synthesis Sign, lattice are applied and thank San Shi diseases, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis side Rope hardening/guam parkinsonism-dementia complex, non-Guam type motor neuron disease, thermophilic with neurofibrillary tangles Argent grain dementia, corticobasal degeneration, with the Diffuse neurofibrillary entanglement of calcification, Frontotemporal dementia, chain In Frontotemporal dementia, Hallervorden Spatz disease, multiple system atrophy, the C of companion's parkinson's syndrome of No. 17 chromosome Glial cells hyperplasia disease, progressive under type Niemann-Pick disease, globus pallidus-ponto-nigral degeneration disease, Pick disease, progressive cortex Paralysis on core, subacute sclerosing panencephalitis, only entanglement type is dull-witted, postencephalitic parkinsonism and myotonic nutrition not It is good.In some embodiments, the present invention provides a kind of method for being used to treat Alzheimer disease (AD).In particular implementation side In case, the present invention provides a kind of for treating the Tau relevant diseases shown in the obstacle of cognitive function or forfeiture or illness Method, the cognitive function is such as inferred, situation judgement, memory capability, study or special navigation.In some embodiments In, methods described includes applying the anti-Tau of effective dose to the individual with any of disease as described above or illness Antibody.In such embodiment, methods described further comprises applying at least one of effective dose for example such as to individual Additional therapeutic agent described below.In some embodiments, methods described is included in disease described herein One of individual apply effective dose anti-Tau antibody.In such embodiment, methods described further comprises to individual Body applies at least one additional therapeutic agent as described below of effective dose.Can according to " individual " of any the embodiment above For people.
On the other hand, the present invention provide it is a kind of be used to reducing Tau albumen in individual (such as total Tau, total soluble T au, Titanium pigment acidifying Tau, total insoluble Tau, insoluble phosphorylation Tau, peroxophosphoric acid Tau or containing peroxophosphoric acid Tau into To helical filament) horizontal method in.For example, such a reduction of Tau protein levels can be in brain (such as the brain skin of individual Matter and/or hippocampus) or celiolymph in observe.In some embodiments, the present invention provides a kind of for reducing paired spiral shell In the horizontal method for revolving fibril.In some embodiments, methods described includes applying the anti-Tau of effective dose to the individual Antibody is to reduce the level of Tau albumen.In some embodiments, " individual " is people.
In some respects, the present invention provides a kind of one or more diseases for being used to mitigate Tau protein related diseases or illness The method of shape；Or for mitigating Tau protein related diseases or illness (any in all disease as described herein or illness Kind, for example, AD) one or more symptoms anti-Tau antibody or include the medicament of anti-Tau antibody.In some respects, it is of the invention A kind of symptom number for being used to reduce Tau protein related diseases or illness or the seriousness for reducing one or more symptom are provided Method；Or for reduce Tau protein related diseases or illness (all any of disease or illness as described herein, Such as AD) symptom number or reduce one or more symptom seriousness anti-Tau antibody or include the medicine of anti-Tau antibody Agent.In one particular embodiment, the symptom of Tau protein related diseases or illness is cognitive disorder.In a specific implementation In scheme, the symptom of Tau protein related diseases or illness is study and/or memory disorders.In a specific embodiment, The symptom of Tau protein related diseases or illness is lost for long-term memory.In a specific embodiment, Tau albumen correlation disease The symptom of disease or illness is dementia.In some embodiments, the symptom of Tau protein related diseases or illness for it is chaotic, irritated, Aggressive, anxious state of mind or aphasis.In some embodiments, the symptom of Tau protein related diseases or illness is one kind Or obstacle or the forfeiture of a variety of cognitive functions, the cognitive function is such as inferred, situation judges memory capability and/or study.This The method that text is provided includes applying to individual (for example, it shows one or more symptoms of Tau protein related diseases or illness) With the anti-Tau antibody of a certain amount of (such as therapeutically effective amount).
In specific aspect, the present invention, which provides, a kind of to be used to keep or increases cognition and memory ability or for slowing down and Tau eggs The method of the loss of memory of white relevant disease or illness correlation；For keep or increase cognition and memory ability or for slow down with The memory of Tau protein related diseases or illness (all any of disease or illness, such as AD as described herein) correlation The anti-Tau antibody of forfeiture or the medicament for including anti-Tau antibody.Method provided herein is included to individual (for example, its display is remembered The one or more symptoms or memory capability for recalling forfeiture reduce) using the anti-Tau antibody of a certain amount of (such as therapeutically effective amount).
In some respects, the present invention provides a kind of side for being used to reduce Tau protein related diseases or the progression rate of illness Method；Or for reduce Tau protein related diseases or illness (all any of disease or illness as described herein, such as AD the anti-Tau antibody of progression rate) or the medicament for including anti-Tau antibody.Method provided herein is included to individual (example Such as, its one or more symptom for showing Tau protein related diseases or illness) apply the anti-of a certain amount of (such as therapeutically effective amount) Tau antibody.
In some respects, the present invention provides a kind of method for being used to prevent Tau protein related diseases or ongoing disease；Or use In prevention Tau protein related diseases or illness (all any of disease or illness, such as AD as described herein) development Anti- Tau antibody or include the medicament of anti-Tau antibody.Method provided herein is included to individual (for example, it, which has, suffers from Tau The risk of protein related diseases or illness) using the anti-Tau antibody of a certain amount of (such as therapeutically effective amount).
In some respects, the present invention provides a kind of method for being used to postpone Tau protein related diseases or ongoing disease；Or use In delay Tau protein related diseases or illness (all any of disease or illness, such as AD as described herein) development Anti- Tau antibody or include the medicament of anti-Tau antibody.Method provided herein is included to individual (for example, it shows Tau eggs One or more symptoms of white relevant disease or illness) using the anti-Tau antibody of a certain amount of (such as therapeutically effective amount).
On the other hand, the present invention provides the pharmaceutical preparation for including any one of anti-Tau antibody provided in this article, its Such as in any above-mentioned treatment method.In some embodiments, pharmaceutical preparation includes anti-Tau antibody provided in this article Any one of and pharmaceutically acceptable carrier.In another embodiment, pharmaceutical preparation includes provided in this article anti- Any one of Tau antibody and at least one additional therapeutic agent for example as described below.
The antibody of the present invention can be used in therapy individually or with other pharmaceutical agent combinations.For example, antibody of the invention can Co-administered with least one additional therapeutic agent.
For example, can be applied according to the composition of the present invention with other combination of compositions comprising additional therapeutic agent, institute State additional therapeutic agent such as biologically active material or compound, such as Protein tau disease and/or amyloidosis (with Ah Involved amyloid or amyloid sample protein (such as amyloid beta protein) are related in Alzheimer's disease One group of disease and illness) drug therapy in used known compound.
In general, the upper reactive compound of other biological may include neuronal transmission reinforcing agent；Psychotropic drug；Second Acetylcholinesterase inhibitor；Calcium channel blocker；Biogenic amine；Benzene phenodiazine sedative；Acetylcholine synthesis, storage or release enhancing Agent；Acetylcholine post-synaptic receptor agonist；Monoamine oxidase-A or-B inhibitor；N-methyl-D-aspartate ester glutamic acid Ester receptor antagonist；Non-steroidal anti-inflammatory drug thing；Antioxidant；Thrombocytin stimulated conductivity receptor antagonist or other therapeutic agents.It is special For fixed, biologically activating agent or compound can be selected from following compound comprising at least one：For the change of oxidative stress Compound, anti-apoptotic compound, metal-chelator, DNA repair inhibitors (such as pirenzepine (pirenzepine) and metabolism Thing), 3-APS (3APS), 1,3- propanedisulfonic acids ester (1,3PDS), secretion ferment activator, β-and gamma-secretase Ferment inhibitor, Protein tau, anti-Tau antibody (including but not limited to WO2012049570, WO2014028777, Antibody disclosed in WO2014165271, WO2014100600, WO2015200806, US8980270 and US8980271), god Through mediator, β-lamellar blocking agent (beta-sheet breaker), anti-inflammatory agent molecule, " atypical antipsychotic agent " (such as chlorine Nitrogen puts down (clozapine), Ziprasidone (ziprasidone), Risperidone (risperidone), Aripiprazole (aripiprazole) or Olanzapine (olanzapine)) or anticholinesterase (ChEI) (such as Tacrine (tacrine), Rivastigmine (rivastigmine), donepezil (donepezil) and/or galanthamine ) and other drugs and nutriment (such as vitamin B 12, cysteine, acetylcholine precursor, ovum (galantamine) Phosphatide, choline, ginkgo (Ginkgo biloba), acetyl-l-carnitine, Idebenone (idebenone), Propentofylline (propentofylline) or xanthine derivative), with binding peptide (including the antibody, especially monoclonal antibody according to the present invention And its active fragment) together, and pharmaceutically acceptable carrier and/or diluent and/or excipient are optionally included, and be used for The specification of disease treatment.
In some embodiments, antibody of the invention can be administered in combination with neurologic agent.Such neurologic agent include (but Be not limited to) specifically bind to antibody selected from following target or other binding molecules (including but not limited to small molecule, peptide, Fit or other protein zygotes)：β secretions ferment, presenilin, amyloid precursor albumen or part thereof, amyloid egg White β peptides or its oligomer or small fiber, death receptor 6 (DR6), advanced glycosylation end product acceptor (RAGE), pa gold albumen And Huntington protein (huntingtin) (parkin)；Nmda receptor antagonist (i.e. Memantine (memantine)), monoamine consumption Agent (i.e. tetrabenazine (tetrabenazine))；Ergoloid Mesylate (ergoloid mesylate)；The anti-pa of cholinolytic stimulated conductivity Gold gloomy sick medicament (i.e. procyclidine (procyclidine), diphenhydramine (diphenhydramine), benzhexol (trihexylphenidyl), benzatropine (benztropine), Biperiden (biperiden) and artane (trihexyphenidyl))；Dopamine stimulated conductivity anti-parkinson medicament (i.e. Entacapone (entacapone), selegiline (selegiline), Pramipexole (pramipexole), bromocriptine (bromocriptine), rotigotine (rotigotine), selegiline (selegiline), ropinirole (ropinirole), Rasagiline (rasagiline), Apomorphine (apomorphine), carbidopa (carbidopa), levodopa (levodopa), pergolide (pergolide), Tolcapone (tolcapone) and amantadine)；Tetrabenazine；Antiphlogistic (including but not limited to on-steroidal Anti-inflammation drugs (i.e. Indomethacin (indomethicin) and other compounds listed above)；Hormone (i.e. estrogen, progesterone and Leuprorelin (leuprolide))；Vitamin (i.e. folate and Nicotinic Acid Amide)；Ground Mei Bolin (dimebolin)；Homotaurine (homotaurine) (i.e. 3- amino propane sulfonic acids；3APS)；Serotonin receptor active regulator (i.e. xaliproden (xaliproden))；Interferon and glucocorticoid or corticosteroid.Term " corticosteroid " includes but is not limited to fluorine For Kathon CG (fluticasone) (including fluticasone propionate (FP)), beclomethasone (beclometasone), budesonide (budesonide), ciclesonide (ciclesonide), Mometasone (mometasone), flunisolide (flunisolide), Betamethasone (betamethasone) and fluoxyprednisolone (triamcinolone)." inhalable corticosteroid ", which means, to be suitable for Pass through the corticosteroid of inhalation delivery.Exemplary inhalable corticosteroid is that fluticasone, beclomethasone dipropionate, cloth replace Resistance to moral, momestasone furoate, ciclesonide, flunisolide and Triamcinolone acetonide.
In some embodiments, one or more anti-amyloid beta (anti-A β) antibody can resist with provided in this article Tau antibody is applied together.It is mono- that the non-limiting examples of such anti-amyloid beta antibodies include crith pearl monoclonal antibody (crenezumab), Suo Lazhu Anti- (solanezumab), shellfish frequency pearl monoclonal antibody (bapineuzumab), A Dukani monoclonal antibodies (aducanumab), sweet replace Shandong monoclonal antibody And BAN-2401 (Biogen, Eisai Co., Ltd.) (gantenerumab).In some embodiments, one or more β- Amyloid aggregation inhibitor can be applied together with anti-Tau antibody provided in this article.Non-limiting exemplary beta amyloid Inhibitors of protein aggregation include ELND-005 (also referred to as AZD-103 or scyllitol), Te La meter Te (tramiprosate) and PTI-80(；ProteoTech).In some embodiments, one or more BACE inhibitor can be with this paper The anti-Tau antibody provided is applied together.The non-limiting examples of such BACE inhibitor include E-2609 (Biogen, Eisai Co., Ltd.), AZD3293 (also referred to as LY3314814；AstraZeneca, Eli Lilly＆Co.), MK-8931 (Wei Lubeisha ) and JNJ-54861911 (Janssen, Shionogi Pharma) (verubecestat).In some embodiments, it is a kind of Or a variety of Tau inhibitor can be applied together with anti-Tau antibody provided in this article.The non-limiting examples of such Tau inhibitor Including methylenum careuleum, LMTX (also referred to as leucomethylene blue or Trx-0237；TauRx Therapeutics Ltd.)、RemberTM (methylene blue or methylene chloride are blue [MTC]；Trx-0014；TauRx Therapeutics Ltd)、PBT2(Prana ) and PTI-51-CH3 (TauPro BiotechnologyTM；ProteoTech).In some embodiments, it is one or more its He can apply anti-Tau antibody together with anti-Tau antibody provided in this article.The non-limiting examples of other such anti-Tau antibody Including BMS-986168 (Bristol-Myers Squibb) and C2N-8E12 (AbbVie, C2N Diagnostics, LLC). In some embodiments, general error folding inhibitors (such as NPT088 (NeuroPhage Pharmaceuticals)) can be with Anti- Tau antibody provided in this article is applied together.
In some embodiments, niacin or Memantine can be included and according to the present invention's according to the composition of the present invention Chimeric antibody or humanized antibody (including antibody, especially monoclonal antibody and its active fragment) together, and optionally include medicine Acceptable carrier and/or diluent and/or excipient on.
In some embodiments, there is provided include " atypical antipsychotic agent " (such as Clozapine, Ziprasidone, Li Pei Ketone, Aripiprazole or Olanzapine) with according to the present invention chimeric antibody or humanized antibody or its active fragment together with and optionally Ground includes pharmaceutically acceptable carrier and/or the composition of diluent and/or excipient, and the atypical antipsychotic agent is used In treating positive and negative psychotic symptoms, including illusion, vain hope, thinking illness (by substantially it is discontinuous, derail, digress from the subject it is aobvious It is existing) and eccentric or mixed and disorderly behavior, and anhedonia, flattening of affect, spirited dull and Social Withdrawal.
In addition to the chimeric antibody or humanized antibody according to the present invention, other chemical combination that can be suitably employed in composition Those compounds of thing disclosed in such as WO 2004/058258 (referring particularly to page 16 and 17), including medicine target (the 36-39 pages), alkyl sulfonic acid and alkanol sulfonic acids (the 39-51 pages), anticholinesterase (the 51-56 pages), nmda receptor are short of money Anti-agent (the 56-58 pages), estrogen (the 58-59 pages), non-steroidal anti-inflammatory drug thing (the 60-61 pages), antioxidant (61- Page 62), peroxidating body multiplication agent activated receptor (PPAR) activator (the 63-67 pages), cholesterol reducing agent (the 68-75 pages), Amyloid inhibitor (the 75-77 pages), amyloid form inhibitor (the 77-78 pages), metal-chelator (78- Page 79), major tranquilizer and antidepressant (the 80-82 pages), nutriment (the 83-89 pages) and increase biology in brain The compound (referring to the 89-93 pages) and prodrug (page 93 and 94) of the availability of upper active material, the file is to quote Mode be incorporated herein, but the compound especially referred in the number of pages referred to above shown.
Such combination treatment referred to above covers combined administration, and (two of which or two or more therapeutic agents are included in In same preparation or independent preparation) and be administered alone, in the case, the administration of antibody of the present invention can apply one or more And/or carry out before additional therapeutic agent while afterwards.In some embodiments, the administration of anti-Tau antibody and additional therapeutic agent Administration each other in about one month, or in about one week, two weeks or three weeks, or at about one day, two days, three days, four days, five days Or carried out in six days.
The antibody (and any additional therapeutic agent) of the present invention can be applied by any suitable means, including parenteral, lung Interior and intranasal administration, and if necessary for being applied in local treatment, including focus.Parenteral infusions include intramuscular, intravenous, dynamic In arteries and veins, intraperitoneal or subcutaneous administration.Any suitable approach (such as by injection, such as intravenous or subcutaneous injection) can be passed through Administration, it is short-term or long-term that this, which is partly dependent on applying,.Cover various administration time-histories herein, including but not limited to Single administration or repeatedly applied after Each point in time, quickly apply and pulsatile infusion.
The antibody of the present invention will be prepared, be administered and applied in a manner of consistent with good medical practice.Examine in this case The factor of worry includes treated particular condition, the specific mammal treated, the clinical condition of few patients, illness and risen Cause, drug delivery site, application process, using other factors known to time-histories and Medical practitioners.Antibody not necessarily, but Prepared together with prevention or the medicament for treating above-mentioned illness are optionally currently used in one or more.Other such medicaments it is effective Amount depends on amount, illness or the type for the treatment of of the antibody being present in preparation and other factors discussed herein above.These medicines Agent with identical dosage described herein and with route of administration as described herein typically to use, or with described herein About the 1% to 99% of dosage uses, or with by rule of thumb/be clinically defined as appropriate any dosage and any approach and use.
In order to prevent or treat disease, the suitable dosage of antibody of the invention (when individually or with other one or more volumes When outer therapeutic agent is applied in combination) by depending on the type of disease to be treated, the type of antibody, the order of severity of disease and the course of disease, It is in order at and prevents still administration of antibodies, previous therapies, the clinical medical history of patient and the reaction to antibody and master for therapeutic purposes The judgement of attending doctor.Disposably or treated after a series of to the appropriate administration of antibodies of patient.Depending on the type of disease and serious Property, no matter being for example administered alone or by continuous infusion by one or many, about 1 μ g/kg to 15mg/kg (such as 0.1mg/ Kg-10mg/kg) antibody can be the initial candidate dosage for being applied to patient.A kind of typical daily dose can be in about 1 μ g/kg In the range of to 100mg/kg or more than 100mg/kg, this depends on factor referred to above.For after a few days or longer During the repetitive administration of time, depending on symptom, typically by continued treatment untill inhibition level needed for disease symptomses generation.Antibody A kind of Exemplary dosage will be in about 0.05mg/kg to about in the range of 10mg/kg.Therefore, can to patient apply about 0.5mg/kg, 2.0mg/kg, 4.0mg/kg or 10mg/kg (or its any combinations) one or more dosage.Such dosage can be applied intermittently With, such as weekly or apply within every three weeks (such as to cause patient to receive about two to about 20 or e.g., from about six dosage Antibody).Initial higher load dosage can be applied, can then apply one or more relatively low-doses.However, other dosage regimens can It can be applicable.The process of this therapy is easy to monitor by routine techniques and measure.
It should be understood that immunoconjugates of the present invention can be used to replace anti-Tau antibody in any above-mentioned preparation or treatment method Or additional anti-Tau antibody is carried out.
H. product
In another aspect of this invention, there is provided containing suitable for treating, preventing and/or diagnosing illness as described above The product of material.The product includes container and on container or with container subsidiary label or package insert.Suitable appearance Device is included such as bottle, bottle, syringe, IV solution bags.Container can be formed by multiple material (such as glass or plastics).Hold Device accommodates single formulation or the composition with another combination of compositions of effectively treatment, prevention and/or diagnosis symptom, and can Mouth (such as container can be with can be by the intravenous solution bag or bottle of the plug of hypodermic injection needle-penetration) is accessed with sterile. At least one of composition activating agent is antibody of the invention.Label or package insert indication composition are selected for treating Symptom.In addition, product can include the first container (a) wherein containing composition, wherein the composition includes the anti-of the present invention Body；Wherein second container containing composition, wherein the composition include another cytotoxic agent or other treatment (b) Agent.Product in this embodiment of the present invention can further comprise that indication composition can be used for the medicine for the treatment of very pathology to say Bright book.Besides or furthermore, the product can further comprise second (or 3rd) container, it includes pharmaceutically acceptable buffering Liquid, such as injection bacteriostatic water (BWFI), phosphate buffered saline (PBS), Ringer's solution (Ringer ' s solution) and dextrorotation Sugar juice.It can further comprise the other materials needed for for business and user's viewpoint, including other bufferses, dilution Agent, filter, pin and syringe.
It should be understood that instead of anti-Tau antibody or in addition to anti-Tau antibody, any said products may also include exempting from for the present invention Epidemic disease conjugate.
III. embodiment
It is below the embodiment of method and composition of the invention.It should be understood that in view of general description presented above, can Implement various other embodiments.
Embodiment 1：Produce the Tau for immunity inoculation
Produce monomer restructuring Tau
By recombined human Tau constructs, 2N4R isotypes (amino acid 2-441) and N-terminal His tag fusions in order to purifying and Characterize.See, for example, Figure 15.Fusion constructs are cloned into pET52b carriers (Novagen), and in expression in escherichia coli. Cell is gathered, and makes its lysis using 7M chlorinations Guanidinium under Denaturing under agitation at 4 DEG C.Continue 1 under 40,000rpm Hour makes cell fragment into spherolite.Pass through nickel affinity chromatography (Ni Sepharose excel affine resins, GE Healthcare Life Sciences), then pass through SEC (resins of Superdex 200, GE Healthcare Life Sciences) protein marked through His labels recombinated is separated under Denaturing.By by institute The protein of recovery is dialysed in the 20mM MES to pH 6.8,50mM NaCl and 1mM TCEP to remove chlorination Guanidinium.Then use TEV protease removes His labels, then using cation-exchange chromatography (Mono S posts, GE Healthcare Life Sciences final purifying) is carried out to remove the His labels of cracking.Purification buffer contains 0.1%Triton x-114 (v/v) To remove endotoxin.Purified protein is replaced by the PBS with 1mM TCEP.Pass through SDS-PAGE and SEC- MALLS purity assays and free state.Status is confirmed by mass spectrum.Pass through the UV absorption measurement protein concentrations at 280nm.Such as Determined by dynamics horseshoe crab ameboid cell lysis liquid (LAL), final product is free of endotoxin (＜ 0.5EU/mg).
Produce phosphorylation Tau
Phosphorylation Tau is produced using the Tau2-441 constructs prepared by method as described above.Use 0.5 μM of PKA Kinases (Life Technologies) carries out phosphorylation to protein construct, and among other residues, PKA kinases makes an ammonia Sour 409 phosphorylations.By reactant mixture and 1mM ATP, 5mM MgCl2Cultivate 72 hours at room temperature together.It is true by mass spectrum Recognize phosphorylation.Kinases is removed using SEC (Superdex 75, GE Healthcare Life Sciences). Purity, free state and the level of endotoxin of phosphorylating protein preparation are substantially analyzed as described above.
Monomer Tau external oligomerization
Oligomerization Tau is produced using monomer Tau2-441 constructs.Monomeric protein is replaced by 20mM N first, N- is double In (2- ethoxys) -2- aminoethane sulphonic acids (BES), 25mM NaCl (pH 7.4), 75 μM of peanuts four are then used at 37 DEG C Olefin(e) acid (Cayman Chemicals) and 18kDa heparin (Sigma Aldrich) the progress oligomerization with protein equimolar concentration Continue 3 days.Oligomerization is confirmed by Thioflavin T fluoremetry, dynamic light scattering (DLS) and analytic type SEC. In some cases, oligomerization Tau is referred to as " few Tau ".
Embodiment 2：Produce anti-Tau antibody
Method
Produce hybridoma
Female C57BL/6JOlaHsd (C57BL/6) and BALB/c OlaHsd (Balb/c) wild type for obtaining 9 week old are small Mouse (Harlan, USA).Obtain the Tau gene knockout mices (B6.129-MapttmlHnd/J of 6 and 9 week old；The Jackson Laboratory, USA).Start vaccine inoculation in 12 to 15 week old.Vaccine inoculation is carried out to mouse with oligomerization people Tau.In vaccine Before inoculation, few Tau is mixed with one of two kinds of adjuvants used in this research：50%v/v Ribi adjuvant systems (Ribi；Sigma-Aldrich, Switzerland), or the single-stranded synthetic DNA oligodeoxynucleotide (CpG of CpG；Microsynth, Switzerland) with aluminium hydroxide (Al；Brenntag, Switzerland) combination.Ribi is in squalene oil, 0.2% (separated in Tween-80 and water containing monophosphoryl lipid A from salmonella minnesota (Salmonella minnesota) Obtain) and the bacillus mycomycete acid esters of trehalose synthesis two (from tubercle bacillus (Tubercle bacillus) cord factor (cord factor) is isolated) 2% water cornerite MF59 fat liquor.
Vaccine inoculation is carried out to mouse by the way that (s.c.) is subcutaneously injected, except D groups and G groups receive intraperitoneal (i.p.) and tooth The combination that pawl is applied.50 μ g widows Tau are applied to the mouse i.p. of D groups and 10 μ g widows Tau are applied with hock injection form.To G groups Mouse i.p. apply and 8 μ g widows Tau and 2 μ g widows Tau applied with hock injection form.Referring to table 2.
For containing 60 μ g (30nmol) containing the vaccine inoculation of CpG and Al (CpG/Al) as adjuvant, each 200 μ L injections CpG, 1mg Al and 50 μ g widows Tau.For all seminar, mouse is carried out at the 0th day, the 14th day, the 35th day and the 56th day Injection.Mouse (Nanotools, Germany) for myeloma fusion is added with the daily few Tau for being not added with adjuvant three times in addition Injection penetrates (each i.p. injects 50 μ g) and carries out vaccine inoculation.
The mouse of table 2. and vaccination protocols
Booster shots three times last time one day after, mouse is drawn blood and put to death, and makes splenocyte and myeloma Cell fusion with obtain produce antibody hybridoma.
Select the hybridoma for subclone
For fusion, by mouse be divided into three groups be used for amount to 10 fusion (in a group 2 merge, in the second set Four fusions, and four fusions in the 3rd group), produce 299 hybridomas.Make hybridization of living using the Selective agar medium containing serum Knurl grows, and then as described below, is combined for total length people Tau and few Tau, is used for sub- gram using ELISA measure selections Grand optimal hybridoma.After limitation dilutes, final hybridoma is then set to be grown in serum free medium, and from stablizing colony Collect culture medium and be used for antibody screening and selection.
ELISA screening test
Serum-free supernatant is gathered from hybridoma is stablized.Supernatant of the screening containing target antibody is then determined by ELISA Liquid antibody characteristic and selects the antibody for further developing to characterize.ELISA determines following for determining：With total length people Tau (flTau；SignalChem, Canada) combination, the combination with peroxophosphoric acid flTau (Genentech, USA), with flTau The combination of oligomerization formulations Comparative's monomer formulation, and and some antibody Tau epitopes combination.In simple terms, with as shown in table 3 One of target coats 96 hole MaxiSorp ELISA culture plates (Nunc, Denmark).
Table 3. is used for the target of ELISA screening test.
It is coated overnight in phosphate buffered saline (PBS) (PBS) at 4 DEG C.It is fully clear with 0.05%Tween-20/PBS Culture plate is washed, and 1 then is blocked to it with the 0.05%Tween-20/PBS containing 1% bovine serum albumin(BSA) (BSA) at 37 DEG C Hour.Then to specify dilution factor to add antibody contained in doma supernatant, and cultivate 2 hours at 37 DEG C, thereafter Culture plate is cleaned as described previously.
For Salmonella, AP combinations are added in 0.05%Tween-20/PBS with 1/6000 dilution factor at 37 DEG C Anti-mouse IgG secondary antibodies (Jackson ImmunoResearch Laboratories, United Kingdom) continue 2 Hour.After final cleaning, by culture plate and p-nitrophenyl disodium hydrogen phosphate hexahydrate (pNPP；Sigma-Aldrich, Switzerland) phosphatase substrate solution is cultivated together, and uses ELISA culture plates reader (Tecan, Switzerland) It is read out at 405nm.As a result it is expressed as optical density (OD) (O.D.).
, will be contained in the sterile doma supernatant of serum-free with 500 times of dilution factors for few Tau and single Tau capturing ELISAs Some antibody is fixed on the culture plate through anti-igg coating, then cultivates few Tau or single Tau, both of which is via AVI labels Acted on locus specificity biotin labeling.Target is cultivated to be started with 5 μ g/mL, and then 8 or 16 times of dilution.Streptavidin- HRP and ABTS substrates are used for the progress signal in culture plate reader (Tecan, Switzerland) and quantified.As a result it is expressed as O.D.。
Affine force evaluating
Pass through surface plasma resonance using Biacore T-100 instruments (GE Healthcare, United Kingdom) Estimate the affinity of antibody not purified in Serum-free Hybridoma supernatant.Antibody is fixed to anti-igg biology sensor core On piece, and target analyte is used as using flTau (SignalChem, Canada).Enter action using 1: 1 Lang Gemiaoer model of fit Mechanical analysis.
SDS-PAGE and Western blotting measure
The non-ad control donor from three AD donors and two age-matcheds is used in immunoblotting (WB) The knot of general Tau antibody and Tau in human brain selected by brain lysate (Tissue Solutions, United Kingdom) test Close.Lysate is processed to obtain the soluble T au fractions of no cleaning agent.Processed lysate is loaded to 4%-12% On bis-tris gels (Novex, Life Technologies, Switzerland) and it is transferred to Immobilon pvdf membranes On, and carry out blotting with the antibody and IRDye 800CW Goat anti-mouse secondaries antibody (Li-Cor, USA) tested.
Determined using the ELISA of human brain lysate
In order to assess selected antibody and AD and the combination for compareing undenatured people Tau in brain lysate, as described above The antibody from doma supernatant or negative and positive control antibodies are made to be fixed on 96 hole culture plates.Then catch and come from AD Or soluble human brain lysate (the 400 μ g/mL protein of age matched control subject；It is all from Tissue Solutions, United Kingdom) in Tau, and use multi-clone rabbit general Tau antibody (AbCam, United Kingdom), then examined using Fc- γ fragments specific anti-rabbit IgG-AP (Jackson ImmunoResearch, USA) Survey.Compareed using the brain lysate from Tau gene knockout mices as negative sample.By culture plate and pNPP (Sigma- Aldrich) phosphatase substrate solution is cultivated together, and is existed using ELISA culture plates reader (Tecan, Switzerland) It is read out at 405nm.As a result it is expressed as optical density (OD) (O.D.).
The sequencing of antibody hybridoma
It is supplied to Antitope (Antitope, United Kingdom) to be used for variable region hybridoma lysate Gene sequencing.In simple terms, using the degenerate primer for muroid signal sequence collect thing with for IgG variable heavy chains (VH), The constant region primers of each of IgM VH chains, Ig κ variable lights (KVL) and Ig λ VL chains carry out RT-PCR together.Use One group there is specific six degenerate primers to collect thing (HA to HF) and IgM or IgG specificity constant regions to VH signal sequences Primer expands to heavy chain V area mRNA together.Collect thing (to κ collection using one group of eight signal sequence specific degenerate primers Group seven (KA to KG) and to λ clusters one (LA)) light chain V area mRNA are expanded together with κ or λ constant region primers.It is right The PCR primer obtained from Successful amplification is purified, and is cloned into ' TA ' cloning vectors (pGEM-T Easy, Promega) In, convert into Escherichia coli and indivedual colonies are sequenced.Antibody VH and VL areas are determined with the sequence of 27 antibody hybridomas Nucleotides and amino acid sequence.
As a result
Select the hybridoma for subclone
Initially (total 299 from ten fusions is miscellaneous for hybridoma caused by measure from each of three-wheel fusion Hand over knurl) with flTau combination, and the combination of hybridoma and pTau and oligomerization Tau selected by determining in addition.Target is selection and Tau With the antibody of the equal good combinations of Tau (such as phosphorylation or oligomerization Tau) of translated rear modification.Therefore, hybridoma is carried out Determine to select optimal general Tau properties.In order to determine antigen-binding site and specificity T au epitopes, first by different Tau pieces Section, and then using the overlapping Tau peptide libraries of 15 aggressiveness of all 441 amino acid (aa) sequences across most long people Tau isotypes To determine land.One group of antibody for being incorporated into predetermined Tau areas is avoided to make posttranslational modification forms different from Tau's intentionally Combination and and people present in the combinations of whole six kinds of different people Tau isotypes maximize.
Three fusion series cause to produce 133 stable hybridomas through subclone, screen its optimal general Tau property.No Combination with screening test is used for the number for reducing the antibody hybridoma to general Tau antibody with preferred property.In order to compare FlTau and pTau is combined, and 90 hybridomas is measured, wherein the result of 24 hybridomas is showed in Figure 1A-F.Due to It is known with highdensity at Alzheimer disease (AD) in selection and Tau to avoid to have carried out initial screening using Tau fragments The antibody combined with the area of the residue of phosphorylation in other Protein tau diseases, therefore as thus ELISA is determined, it is most of to be tested Antibody flTau and pTau are incorporated into similar binding property.
In some embodiments, it is desired to general Tau antibody bindings in both Tau monomer and oligomerization form without it is strong partially Good one or another one.Capturing ELISA is set both in the form of determining antibody and whether be incorporated into flTau monomer and oligomerization.With Compared when (wherein target is fixed on ELISA culture plates) is run in the form of Salmonella, the ELISA run with trap mode Tau oligomer conformation and single Tau free state preferably before protection oligomerization.
Each measure is carried out by directly comparing the combination of two kinds of Tau forms and whole 90 kinds of antibody tested.It is known Preference is incorporated into any few Tau or nondistinctive antibody is used as compareing in each measure between two kinds of Tau forms.18 hybridization The result of knurl is showed in Fig. 2A-E.
Epitope is positioned for selecting the antibody with good general Tau properties most important because can avoid with have it is highly dense Spend the antibody that the area of potential pTau residues (Ser, Thr and Tyr) combines.And the combination of people Tau all six kinds of isotypes is also used Make the selection standard of general Tau antibody.With improved precise verification and the antibody initially selected is determined using the library of 49 kinds of peptides General Tau epitopes, across the people Tau total lengths of peptide each have 15 amino acid (aa), wherein 6 aa residues are overlapping and 9 aa Skew.Most long isotype (441 aa) of the residue numbering based on people Tau.Contrast is not associated with all peptides, with higher 1/10 dilution Spend using not purified antibody to verify combination.From previously passed ELISA selection 112 hybridoma screening antibodies instruction with 20 different Tau epitopes combine (table 4).
Table 4：For the Tau epitopes of antibody
For being measured with flTau affinity, 46 kinds of antibody are measured using SPR on Biacore instruments, wherein determining KD.By the way that antibody is fixed on anti-igg chip and Biacore affinity measurements are carried out using flTau as target analyte. The result of 32 kinds of antibody is showed in table 5, wherein being sorted out based on the affinity with flTau to antibody.In measurement and flTau parent In the antibody of power, the affinity of 22 kinds of antibody is better than 20nM, wherein the K of 14 kinds of antibodyDLess than 5nM, wherein antibody 37D3-H9 KD(affinity) is 1nM.
Table 5：To flTau affinity
In order to verify the combination of selected antibody and people Tau all six kinds of isotypes, with containing six kinds of isotypes of whole Tau ladders operation SDS-PAGE is recombinated, and immunoblotting (WB) is carried out using Tau antibody selected by three kinds.All three General Tau antibody bindings are in all six kinds of Tau isotypes (Fig. 3).In addition, run simultaneously from three AD and two age-matcheds The brain homogenate of control is for comparing.As expection and based on the epitope positioned, all three tested in this measurement resists Body is shown and all combinations of six kinds of Tau isotypes.In mankind AD and the difference that is observed in compareing between donor with pattern It is different to represent larger phosphorylation and/or the stable Tau aggregations of the expected SDS being present in AD subject.
People's Alzheimer disease (AD) and control sample are run to verify and people in non denatured ELISA catches measure in addition Tau combination in brain.With the operation of 8 times of dilution factors for the control subject from two AD and two non-ad age-matcheds can The sample lysate that dissolubility Tau is processed, so as to test three kinds of antibody (Fig. 4 A-C).
Determine the antibody variable chain-ordering (Antitope, United Kingdom) of 27 hybridomas.Some heavy chains and light Chain variable domain and hypervariable region (HVR) protein sequence are showed in sequence table.
Embodiment 3：Characterize anti-Tau antibody
It is subcloned via gene chemical synthesis and by gained DNA to muroid IgG2a (heavy chain) and muroid κ (light chain) mammal table Heavy chain of antibody and light chain are built up in carrier.By transient cotransfection heavy chain and light chain plasmids come in CHO or 293T cells Antibody is expressed, and is purified with affine resin MabSelectSure (GE Healthcare Life Sciences). On Biacore T200 surface plasma resonance instrument devices kit and S series CM5 chip pins pair and Tau are caught using mouse IgG Purified recombinant antibodies are screened in the combination of monomeric protein.Using 10 μ l/min flow velocity, catch 1 μ g/ml concentration with MIgG2a forms are diluted in 10mM HEPES (pH 7.4), 150mM NaCl, 0.05%Tween 20 (operation buffer solution, HBSP) In antibody continue 30 or 45 seconds (antibody 26C1,94B2-C1,52F6-F11.v1,52F6-F11.v2,11E10-B8,55E7- F11,125B11-H3,123E9-A1,30G1-B2,66F5-A1,89F4-A1,93A8-D2 and 126F11-G11), or catch 0.1 The antibody of μ g/ml concentration continues 70 or 150 seconds (antibody 19H6-F7,3A4-H4,54C1-H11 and 37D3-H9).At 25 DEG C Use combination of the 30 μ l/min flow velocity and following concentration monitor Tau monomers in HBSP：For antibody 26C1 and 94B2,16, 31st, 63,125,125,250 and 500nM；For antibody 52F6-F11.v1 and 52F6-F11.v2,16,31,63,125,125, 250th, 500 and 1000nM；For antibody 11E10-B8,55E7-F11 and 125B11-H3,6,19,56,56,167 and 500nM；It is right In antibody 123E9-A1,30G1-B2,66F5-A1,89F4-A1,93A8-D2 and 126F11-G11.5,16,49,148,148, 444th, 1333 and 4000nM；For 19H6-F7,0.4,1.6,6.3,2.5,100 and 400nM；With for 3A4-H4,54C1-H11 And 37D3-H9,0.2,0.8,4,4,20 and 100nM.Monitoring association time and Dissociation time continue 180-480 seconds and 300- respectively 600 seconds.It is attributed to high-affinity (table 6) and NXS/T glycoylation motifs is not present in CDR and select antibody 37D3-H9 to be used for Further analysis.
Table 6：The K of rodent antibody and people's Tau monomersD(nM).Shown data represent the output valve of 1: 1 binding model.
37D3-H9 shows affinity when being incorporated into Tau albumen
Monomer Tau albumen and Biacore S systems are made one using Biacore amine coupling reagents box (GE Life Sciences) Arrange CM5 chip covalent couplings so that fixed with about 128RU level.Using single cycle dynamic experiment mode monitoring Fab and The 37D3-H9 of IgG forms directly in conjunction with wherein five association periods are respectively 300s, and antibody concentration is 1,2,4,8 and 16nM (IgG) or 5,10,20,40 and 80nM (Fab).Monitoring dissociation continues 7200 seconds (Fab) or 14400 seconds (IgG).With 1: 1 Binding model fitting data calculates dissociation rate value.The dissociation rate calculated is 5.0 × 10 to 37D3-H9Fab-4It is and right 37D3-H9IgG is 1.1 × 10-5, differ 45 times.Fig. 5 illustrates the difference of Fab (left figure) and IgG (right figure) dissociation rate, instruction 37D3-H9 IgG show affinity.
Embodiment 4：The humanization of anti-Tau antibody
Shared by the way that antibody CDR and selected variable region Framework residues are migrated into human antibody on framework to make antibody 37D3- H9 humanizations (Dennis, M.S. (2010) .CDR repair：A novel approach to antibody humanization.Current Trends in Monoclonal Antibody Development and Manufacturing, S.J.Shire, W.Gombotz, K.Bechtold-Peters and J.Andya, compile (Springer, New York), the 9-28 pages).Assess to the transplanting on shared VH3, V κ 2 and the frameworks of V κ 1.In position 49, (Kabat is compiled heavy chain graft Number system) place includes muroid residue.The grafts of V κ 2 include muroid residue in framework positions 2 and 4.The grafts of V κ 1 are in framework position Putting 2,4 and 43 includes muroid residue.Expressed and carried to human IgG1 or IgG4 and κ chains mammal by gene chemical synthesis and subclone Humanization variants are built in body.By the way that heavy chain and light chain plasmids cotransfection expressed into antibody into Chinese hamster ovary celI, and with affine Resin M abSelect Sure are purified.Kit, S series CM5 chips and Biacore are caught using Biacore human IgGs T200 instruments are directed to screens humanization variants with the affinity of people's Tau monomers.Antibody is diluted to 2 μ g/ml, and in 10 μ l/min It is lower to catch 15 seconds.Under 30 μ l/min flow velocity, monitoring 100,33,11 and 3.7nM people Tau monomers are in 10mM HEPES (pH 7.4), 150mM NaCl, the association in 0.05%Tween 20 (operation buffer solution, HBSP) and dissociation continue respectively 180 seconds and 600 seconds.1: 1 binding model (table 7) is applied to result.
Table 7：Screened for the affinity of monomer people Tau humanization variants
Further characterized by surface plasma resonance in the case of other antibody concentrations and longer association/Dissociation time Antibody variants hu37D3-H9.v1, hu37D3-H9.v2, hu37D3-H9.v5 and hu37D3-H9.v6.With the people of wider range Tau monomer concentrations (1.2,3.7,11.1,11.1,33.3,100nM) and it is increased association (300 seconds) and dissociate (1200 seconds) when Between piecewise analysis these variants.1: 1 binding model (table 8) is applied to result.
Table 8：Pass through variant selected by surface plasma resonance labor and people Tau binding kineticses
YTE (M252Y/S254T/T256E) mutation are incorporated into some IgG4 antibody.Neonatal Fc receptor has been described (FcRn) binding structural domain mutation such as M252Y, S254T and T256E (YTE) increase FcRn are combined and therefore increase antibody partly declines Phase.Referring to US publication application the 2003/0190311st and Dall ' Acqua et al., J.Biol.Chem.281： 23514-23524(2006)。
Antibody 125B11-H3 humanizations to VH3 and V κ 1 are shared on framework.In position 78, (Kabat is compiled heavy chain graft Number system) place includes muroid residue.The grafts of V κ 1 include muroid residue in framework positions 43 and 87.Also by 113F5-F7's It is light chain humanized on the frameworks of V κ 1, it has extra muroid residue at framework positions 43 and 87.By humanization variants heavy chain (125B11) and light chain (125B11 and 113F5-F7) cotransfection in the form of multiple combinations, and as retouched above in 96 orifice plate lattice State and purified.Then kit, S series CM5 chips and Biacore T200 instruments is caught using Biacore human IgGs to be directed to Humanization variants are screened with the affinity of people's Tau monomers.Antibody is diluted to 2 μ g/ml, and caught 15 seconds under 10 μ l/min. Under 40 μ l/min flow velocity, the association and dissociation of monitoring 0,100 and 500nM people's Tau monomers in HBSP continue 180s respectively And 300s.1: 1 binding model (table 9) is applied to result.
Table 9：125B11-H3 and 113F5-F7 humanization variants are screened by surface plasma resonance
* the minimum with Tau monomers combines
NT, do not test.
Based on affine screening (table 10) selection variant hu125B11.v17 (HC3+LC1), hu125B11.v26 (HC4+LC2) It is used for high-resolution dynamic analysis with hu125B11.v28 (HC4+LC4).By antibody 94B2-C1 humanizations to the structures of VH1 and V κ 2 On frame.Heavy chain graft also includes muroid residue at position 28,29,67,69,71 and 73 (Kabat numbering systems) place.V κ 2 are moved Plant also includes muroid residue in framework positions 2,36 and 46.The combination of eight heavy chains and eight light chains is expressed, it is such as right above In described by 125B11, purified and screened by surface plasma resonance (SPR).The result of SPR screenings is showed in table 11 In.Select variant hu94B2.v105 (heavy chain mutant 94B2.HC1, light chain variant 94B2.LC13) to be used for detailed SPR and characterize (table 11)。
Table 10：The dynamics data of the selected anti-Tau antibody variants of humanization
Table 11：94B2 humanization variants are screened by surface plasma resonance
* the n=3 average value repeated.
hu94B2.v105。
§Observe and combined with the minimum of Tau monomers.
NT, do not test.
Embodiment 5：The stability analysis of Tau antibody anti-to humanization
Differentiate chemical instability
Heat stress is carried out to antibody samples to simulate the stability within product storage period.Sample Buffer is replaced by 20mM In acetate buffer (pH 5.5) or phosphate buffer (pH 7.4), and it is diluted to 1mg/ml concentration.1ml samples are made to exist It is subjected to that 2 weeks stress be continued at 40 DEG C, and second sample is stored at -70 DEG C as control.Pancreas is used with latter two sample Protease is digested to produce peptide, liquid chromatography (LC)-mass spectrum (MS) analysis can be used to analyze peptide.For sample In each peptide, the holdup time (from LC) and high-resolution accurate mass and peptide ion fragmentation information (amino is obtained in MS Acid sequence information).Under ± 10ppm window, according to data set, carrying for target peptide (peptide ion primary and through modification) is obtained Take chromatography of ions figure (XIC) and peak is integrated to determine area.By by (area of the peptide through modification) divided by (through modification The area of peptide add the area of primary peptide) be multiplied by 100 to calculate the relative modification percentage of each sample.Then in control (t=0) Sample with stress between (t=2 weeks) sample compared with these relative percentages.Shown percentage represent stress (t=2 weeks) value subtract Compare (t=0) value.Desamidization analysis to antibody hu37D3-H9.vl and hu37D3-H9.v5 causes to observe light chain CDR- Sequence N in 128G29N30(Kabat numberings) is easy to desamidization.It was found that deamidation N28G29N30Increase for hu37D3- H9.v1 is 16.5% and is 11% for hu37D3-H9.v5.
The influence of combination of the desamidization to antibody and antigen
To assess N28The influence of desamidization pair and people Tau affinity is, it is necessary to obtain N28Desamidization state interval compared with Two wide samples.At 40 DEG C by Hu37D3-H9.v5hIgG4.S228P with 1mg/ml concentration in phosphate buffered saline (PBS) Cultivated two weeks in (pH 7.4).N is measured using LC-MS/MS28G29The desamidization of motif.Relative to t=0 not stress sample, t =2 weeks stress sample desamidization increase by 43.1%.Kit and S series CM5 cores are caught using GE Biacore human IgGs Piece by surface plasma resonance (Biacore) analysis stress with not stress antibody Tau combine.By hIgG in 10mM 2 μ g/ml are diluted in HEPES (pH 7.4), 150mM NaCl, 0.05%Tween 20 (operation buffer solution, HBSP), and 10 Caught under μ l/min flow velocity 15 seconds (t0 samples) or 17 seconds (t2 samples).Using 30 μ l/ flow velocity, 300s association the stage and 1800s dissociates the stage, collects mono- with the people Tau of in HBSP 0,3.1,6.3,12.5,25,25,50 and 100nM concentration injection The dynamics data of body.Between each circulation, make surface regeneration using injections in 30 seconds of 3M magnesium chlorides with 10 μ l/min.Use instrument 1: 1 binding model fitting data of device default parameters (local fit for including " RI " parameter).Result shown in Fig. 6 and table 12 Show, although in this experiment, stress antibody with than not stress the high level of antibody it is fixed, the magnitude of Tau binding signals is (such as Represented by parameter Rmax magnitude) it is significantly lower., stress after being standardized for the horizontal difference of seizure to Rmax values (t=2 weeks) sample seem to be shown as not stress the total Tau binding abilities of sample it is only about half of (by standardize Rmax reduce by 56% Instruction).The affinity calculated seems unchanged：In this analysis, the K between t=0 and the sample of t=2 weeksDDifference is less than 2% (for t=0 and t=2 weeks, KD=0.7nM).As a result it is consistent, wherein the sample of t=2 weeks contains the height substantially reduced Affinity antibodies colony.
Table 12：By surface plasma resonance obtain stress with stress not hu37D3-H9.v5 samples and monomer Tau It is relative to combine
The influence of combination of the desamidization to antibody and antigen and " standardization Rmax " calculating
In view of expected asparagine desamidization produce aspartic acid and different aspartic acid product (BischoffR. and Kolbe H.V.J. (1994) .J.Chromat.5,662, the 261-278 pages), analyze N28It is replaced into D28(variant hu37D3- H9.v5N28D) the influence pair with the affinity of people's Tau monomers.Biacore T200 instruments, GE Biacore are used at 25 DEG C Human IgG catches kit and CM5S family chips assess affinity.By hIgG in 10mM HEPES (pH 7.4), 150mM 2 μ g/ml are diluted in NaCl, 0.05%Tween 20 (operation buffer solution, HBSP), and 22 are caught under 10 μ l/min flow velocity Second.Using 30 μ l/min flow velocity, 300 seconds association stage and 600 seconds dissociation the stage, collect with 0 in HBSP, 6.3,12.5, 25th, the dynamics data of people's Tau monomers of 25,50,100,200 and 400nM concentration injection.Between each circulation, with 10 μ l/ Min makes surface regeneration using injections in 30 seconds of 3M magnesium chlorides.With 1: 1 binding model fitting data, and use dynamic analysis meter Calculate hu37D3-H9.v5 and hu37D3-H9.v5.3 (referred to herein as hu37D3-H9.v5N28D) affinity.For 1: The parameter of 1 fitting includes the instrument default parameters of the local fit of " RI " parameter.As a result it is showed in Fig. 7 and table 13.
With the hu37D3-H9.v5 K for analyzing to obtain under the same conditionsDCalculated value 1.5 × 10-9M (average value, n=4 times Determined in experiment) compare, the K of hu37D3-H9.v5N28D variantsDCalculated value is 160 × 10-9M.Therefore, N28It is converted into D28 Affinity is caused to reduce 100 times of ＞.In view of relatively low affinity and the relatively fast power of hu37D3-H9.v5 N28D variants Learn, it is concluded that to N28And D28The dynamic analysis of variant mixture will be and relatively low affine by higher affinity collective control The presence of power variant can be reflected by the reduction for standardizing Rmax.In order to verify this deduction, by antibody variants hu37D3-H9.v5 and The Tau combination overviews of both antibody of the hu37D3-H9.v5 N28D Tau combination overviews together with mixed in equal amounts are compared Compared with.Compared with independent hu37D3-H9.v5, hu37D3-H9.v5 and hu37D3-H9.v5 N28D 1: 1 mixture causes mark Standardization Rmax reduces by 45% (table 13).We conclude that may indicate that stress sample for changes of the standardization Rmax after heat stress Middle high-affinity antibody colony is reduced.It is concluded that standardization Rmax change is therefore stability-enhanced available for screening Hu37D3-H9 variant.
Table 13：After hu37D3-H9.v5 heat stress and in hu37D3-H9.v5 and expected deamidated products The standardization Rmax observed after hu37D3-H9.v5 N28D mixing change
* Rmax=Rmax (RU)/ligand level (RU) is standardized.Standardization Rmax=0.33 (four realities of reference antibody Test the average value of interior measure, standard deviation ＜ 0.01).
Antibody optimizes and selection
90 kinds of 37D3-H9 variants are assessed by Biacore undergoing to compare them or do not suffering from two weeks 40 DEG C of heat stresses Functional stabilization in the case of period.Variant includes N28G29N30T31Most of single mutation of motif, contain G29A mutation Double mutant, Asn-28 and Tyr-32 double mutations (can functionally by these group displacements be hydrogen bond knot residue) with And residue 2,4,33 and 93 (as the residue being present in original 37D3-H9 antibody or corresponding system genitale residue variant) is all May arrangement.In addition, in the case of residue 1 is Asp or Glu test mutation, its do not influence the affinity of Asn-28 residues or Stability.
Antibody is expressed by transiently transfecting Expi293 cells in 96 orifice plate lattice, and with 500 μ L MCA96 heads The liquid processing systems of Tecan freedom EVO 200 on purified automatically.In simple terms, 20 μ L are filled with using customization The top post (Glygen Corp＆GE Healthcare) of MabSelect SuRe resins catches the IgG in 1mL cultures. After being cleaned with 1X PBS (pH 7.4), IgG is eluted in 160 μ L 50mM phosphoric acid (pH 3) and with 12 μ L 20X PBS (pH 11) neutralize.MabSelect SuRe tops post is stripped in O.1M NaOH, and is regenerated with 1X PBS (pH 7.4) continuously to make With up to 15 times.Antibody purified in 96 orifice plate lattice is normalized to using Hamilton Star liquid handling robots 0.1mg/ml.Will " stress before " sample is maintained at about 4 DEG C, and is trained " stress be " sample afterwards at 40 DEG C in PCR machines Educate two weeks.Compare variant by using " stress before " and " stress be afterwards " antibody preparation running surface plasma resonance dynamic experiment Functional stabilization.Using as GE Biacore IgG catch kit caused by human antibody catch CM5 S family chips and Biacore T200 instruments assess antibody.The antibody for making to be diluted to 2 μ g/ml using 15 second injection time and 10 μ l/min flow velocitys It is fixed.Using 40 μ l/min flow velocity, monitored at 25 DEG C and the combination of 0nM, 26.5nM and 265nM Tau monomers continues 180 In association stage second, then dissociate the stage within 300 seconds.Using multi-cycle kinetics model in 10mM HEPES (pH7.4), 150mM Run sample in NaCl, 0.05%Tween 20 (HBSP).Using BIAevaluation software analysis datas, fitting 1: 1 combines Model.Gained affinity (KD) value is showed in Fig. 8 A-D.Also use following first principles computations stability index：It is it is expected that affine The impaired antibody (desamidization for being attributed to such as Key residues) of power is equal to IgG seizure horizontal (" ligand level ") contribution, But it is smaller to measured Tau combination contributions, and this will be reflected in the Rmax values of experiment.It is each in order to consider to catch The change of the amount of antibody, by Rmax for antibody capture it is horizontal (such as by " ligand level ", the reaction of immobilization during antibody capture Measured by unit) it is standardized.Therefore, Rmax is standardized with Rmax experiment values (unit=RU) divided by " ligand level " (table Show the RU assessment output valve caught during hIgG catches step, unit=RU) calculate, and stability index here with Standardize Rmax (stress afterwards) divided by standardization Rmax (stress before) calculating.
Selected antibody is expressed by transiently transfecting Chinese hamster ovary celI, and it is purified.Then use RCM trypsase Peptide positions, and in the case where DTT reduction, IAA end-blockings and pH 8.2 digest, antibody is carried out under 1mg/ml to continue two Week, and desamidization is analyzed by LC-MS/MS.As a result (table 14) proves, variant hu37D3-H9.v28.A4 is to N28G29N30Base The sensitiveness of desamidization reduces in sequence.Hu37D3-H9.v28.A4 desamidization reduction is unexpected, because residue is uncertain In Asn-28 residue immediate areas (Fig. 9), and do not know how F33L mutation can make Asn-28 stable.
Table 14：Hu37D3-H9.v28.A4 variants are in it stress test to the stability of desamidization
Embodiment 6：The anti-Tau antibody selection of humanization and sign
Antibody is selected and characterized：And the combination of people's Tau albumen
At 25 DEG C kit and CM5 S family chips are caught using Biacore T200 instruments, GE Biacore human IgGs The affinity of antibody selected by assessment.By hIgG in 10mM HEPES (pH 7.4), 150mM NaCl, 0.05%Tween 20 (behaviour Make buffer solution, HBSP) in be diluted to 0.25 μ g/ml, and caught 150 seconds under 10 μ l/min flow velocity.Use 30 μ l/min's Flow velocity, dissociation stage in 300 seconds associations stages and 600 seconds, collect with HBSP 0,0.4,1.2,3.7,11,11,33 and 100nM's The dynamics data of people's Tau monomers of concentration injection.Between each circulation, sequentially 3M magnesium chlorides twice are used with 10 μ l/min Injection in 30 seconds makes surface regeneration.Data are fitted 1: 1 binding model (table 15).
Table 15：The dynamics data of the selected anti-Tau antibody variants of humanization
Antibody characterization：In the form of hIgG4.S228P.YTE and people's Tau albumen combination
At 25 DEG C kit and CM5 S family chips are caught using Biacore T200 instruments, GE Biacore people FAb Assess affinity.By hIgG 10mM HEPES (pH 7.4), 150mM NaCl, 0.05%Tween 20 (operation buffer solution, HBSP 0.5 μ g/ml are diluted in), and are caught 180 seconds under 10 μ l/min flow velocity.Using 30 μ l/min flow velocity, 300 seconds Association stage and 600 seconds dissociate the stage, collect with HBSP 0,0.4,1.2,3.7,11,11,33 and 100nM concentration injection The dynamics data of people's Tau monomers.Between each circulation, using sequentially injections in 60 seconds of 10mM glycine (pH 2.1) make twice Surface regeneration.Data are fitted 1: 1 binding model.Dynamics data is showed in table 16.
Table 16：Hu37D3-H9.v28.A4 hIgG4.S228P.YTE and monomer people are obtained by surface plasma resonance Tau binding kineticses
Antibody characterization：And the combination of machin Tau albumen
At 25 DEG C kit and CM5 S family chips are caught using Biacore T200 instruments, GE Biacore human IgGs Assess affinity.By hIgG 10mM HEPES (pH 7.4), 150mM NaCl, 0.05%Tween 20 (operation buffer solution, HBSP 2 μ g/ml are diluted in), and are caught 15 seconds under 10 μ l/min flow velocity.Collect between 1.2 and 100nM most The dynamics data of people's Tau monomers of few five different non-zero concentration (wherein with a repetition concentration) injections.Use 30 μ l/ Min flow velocity, 300 seconds association stage and 600 seconds dissociation Stage evaluation dynamics.Between each circulation, with 10 μ l/min stream Speed carries out 30 seconds regenerative injections of 3M magnesium chlorides.Result is fitted 1: 1 binding model.Dynamics data is showed in table 17.
Table 17：Affinity of the anti-Tau antibody of humanization to monomer machin Tau
Humanized antibody hu37D3.v28.A4 and hu37D3.v28.F1 are also incorporated into phosphorylation Tau (pTau).
Embodiment 7：The pharmacokinetics of anti-Tau antibody
In order to assess pharmacokinetics inside anti-Tau 37D3-H9 mIgG2a antibody, to conscious mouse with (IV) in single dose intravenous or intraperitoneal (IP) fast injection is administered to C57BL/6 mouse by 10mg/kg dosage.Grow upon administration During up to the Each point in time of 28 days, plasma sample is collected to determine anti-Tau antibody concentrations.
The concentration of the antibody given given in mice plasma is measured as follows with general ELISA：Use the anti-muIgG2a antibody of mouse Coating, then addition originate in the plasma sample of 1: 100 dilution factor, and end to add the anti-muIgG2a- biotin-conjugateds of mouse Thing and then add the Streptavidin being conjugated for detection with HRPO.The standard curve range of the measure is 1.56-200ng/mL, and it is 0.16 μ g/mL to detect limit value.Less than this detection limit value result be reported as be less than can report value (LTR)。
Figure 10 shows anti-Tau 37D3-H9 mIgG2a pharmacokinetic analysis result.Anti- Tau 37D3-H9 mIgG2a Exposure and clearance rate in wild type C57BL/6 mouse is similar with isotype control Ab, wherein clearance rate be 6.31mL/ days/ kg。
In order to assess pharmacokinetics inside anti-Tau 94B2-C1 mIgG2a and anti-tau 125B11-H3 mIgG2a, Single IP fast injections with from 10mg/kg dosage to conscious C57BL/6 mouse administration of antibodies.It is up to 28 days upon administration Each point in time when, collect plasma sample to determine anti-Tau antibody concentrations.
The concentration of the antibody given given in mice plasma is measured as follows with general ELISA：Use the anti-muIgG2a antibody of mouse Coating, then addition originate in the plasma sample of 1: 100 dilution factor, and end to add the anti-muIgG2a- biotin-conjugateds of mouse Thing and then add the Streptavidin being conjugated for detection with HRPO.The standard curve range of the measure is 0.78-100ng/mL, and it is 0.078 μ g/mL to detect limit value.Also concentration is measured as follows with specific ELISA：Use restructuring Tau originates in the plasma sample of 1: 10 dilution factor as coating, then addition, and ends at addition for detecting and horseradish mistake The conjugated anti-mIgG2a of goat of oxidizing ferment.The standard curve range of the measure is 0.078-10ng/mL, and detects limit value and be 0.0008μg/mL.Less than this detection limit value result be reported as be less than can report value (LTR).
The result of those experiments is showed in Figure 16 and 17.When carrying out analytical concentration using general measure, anti-Tau 94B2 Exposures and clearance rate of the mIgG2a in wild type C57BL/6 mouse are similar with isotype control Ab, but are surveyed when using specificity When carrying out analytical concentration surely, it exposes relatively low and removed very fast.Referring to Figure 16.It is by the general clearance rate for determining measure 4.06mL/ days/kg, and the clearance rate determined by specific assay is 7.53mL/ days/kg.These results show that antibody can be with Time undergoes variation in vivo, and the change damages its ability for identifying its target.No matter which kind of measure produces concentration, anti-Tau Exposures and clearance rate of the 125B11-H3 mIgG2a in wild type C57BL/6 mouse are similar with isotype control Ab.Referring to figure 17.Clearance rate by general measure measure is 4.96mL/ days/kg, and the clearance rate determined by specific assay is 4.90mL/ days/kg.
Table 18 shows the pharmacokinetic parameter of anti-Tau antibody 37D3-H9,94B2-C1 and 125B11-H3 in mouse.
Table 18：The pharmacokinetic parameter of anti-Tau antibody
In order to assess hu37D3.v28.A4hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE antibody Internal pharmacokinetics, single IV fast injections are applied by machin (machin with 1mg/kg dosage to conscious monkey (Macaca fascicularis)).When being up to the Each point in time of 49 days upon administration, plasma sample is collected to determine anti-Tau Antibody concentration.
The concentration of the antibody given given in monkey blood plasma is measured as follows with general ELISA：Applied using goat anti-human's IgG antibody Layer, then addition originate in the plasma sample of 1: 100 dilution factor, and end at addition and sew for what is detected with HRPO The Goat anti human IgG of conjunction.The standard curve range of the measure is 0.156-20ng/mL, and it is 0.02 μ g/mL to detect limit value.It is low In this detection limit value result be reported as be less than can report value (LTR).
Figure 11 displaying hu37D3.v28.A4 hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE medicine For dynamic analysis result.In fig. 11, each group of data point represents a kind of animal, and line represents all dynamic in antibody and measure group The average value of thing.Table 19 shows that hu37D3.v28.A4 hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE exist Pharmacokinetic parameter in machin.
Table 19：Hu37D3.v28.A4 hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE are in machin In pharmacokinetic parameter
Embodiment 8：The further epitope characterization of anti-Tau antibody
After relatively 37D3-H9 and biotinylation Tau monomers and biotinylation peptide of phosphorylation (MAPT_10-24), also it have evaluated 37D3-H9 and other biological elementization peptide combination.It is used at 4 DEG C in 50mM sodium carbonate buffers (pH 9.6) and is diluted to 2 μ g/ The ml hole micropore culture plates of neutravidin coating Nunc maxisorp 96, keep ＞ 12 hours.All follow-up trainings Educate and carry out at room temperature.After coating, Superblock is usedTM(PBS) Block buffer (Thermo Fisher Scientific) culture plate is closed two hours, then fully cleaned with PBS, 0.05% polysorbate20.It is then that hole is sudden and violent It is exposed in 1 μ g/ml biotinylation Tau peptides (table 20) or Avi tagged biotin Tau monomers and continues one hour, and as previously Cleaned.Using each peptide of standard solid-phase Fmoc chemical syntheses (see, for example, Fmoc solid phase peptide synthesis：A practical approach；Chan, W.C., White, P.D. are compiled；Oxford University Press：New York, 2000).Make in 90%SuperblockTM(PBS) in Block buffer from 500nM serial dilutions to 50pM antibody 37D3-H9mIgG2a and hu37D3-H9.v5 hIgG1 combines the hole with biotinylation Tau coatings, keeps 90min.As previously cleaned each hole, and Superblock is diluted in 1/1000TMBeing conjugated through peroxidase in Block buffer Secondary antibody (Invitrogen/Life Technologies) detect binding antibody (respectively with rabbit anti-mouse IgG or goat Anti-human igg (H+L)).After 20min, each hole is such as previously cleaned, and signal is produced with TMB micropore bi-component substrates (KPL).Pass through Addition 1M phosphoric acid carrys out stopped reaction, and measures the absorbance at 450nm with SpectraMax M2 reading plates.
Table 20：Peptide sequence
The result of the experiment is showed in Figure 12.Combination of each of the antibody to specified polypeptide is specified in Figure 12 A displayings.It is anti- Body 37D3-H9 and 94B2-C1 both of which show the strong combination to fragment 10-24, and antibody 94B2-C1 is also showed that in this experiment Strong combination to fragment 1-15.Strong combination of antibody 19F8-C11 and the 123E9-A1 displaying to fragment 19-33, and antibody 89F4- A1 shows the strong combination to fragment 28-42 and 37-51.Referring to Figure 12 A.Antibody 37D3-H9 mIgG2a and hu37D3-H9.v5 HIgG1 both of which shows the strong combination to Tau fragments 2-24 and 2-34, and to fragment 10-24 relatively weak binding.Referring to Figure 12 B And 12C.These results indicate that maturation protein ammonia in antibody 37D3-H9 mIgG2a and hu37D3-H9.v5 hIgG1 combinations Tau Epitope in base acid 2-24.
In Alanine-scanning substitution experiment, it is found that mutation Y18A and L20A eliminates rodent antibody 37D3-H9 to Tau fragments The combination of (fragment 2-21), show that antibody contacts these Tau residues.Peptide is offset using a series of 15 aggressiveness, finds rodent antibody Combination of the 37D3-H9 displayings to fragment 9-23 is similar to the combination to fragment 10-24, and also show that to fragment 7-21,8-22 and 11-25 moderate combines.
Embodiment 9：The sign based on cell of 37D3-H9 humanized antibodies
Method
Primary hippocampus and microglia cell culture and hippocampus-microglia cell coculture
Dissociative type primary hippocampal neuron is prepared by the 16-17 days embryonic period, embryonic phases wild type C57BL/6N mouse.By cell with 25,000 cells/wells paving be applied to through the coating of PDL/ laminins 8 hole chamber slides (Biocoat, On 354688Corning).Cell is spread and applies and is maintained in NbActiv4 (BrainBits), and biweekly changes half training Support base.In 18 cell divisions, restructuring Tau and antibody are applied in culture.
For microglia cell culture, make the cortex from the 1-2 days postpartum C57BL/6N mouse and hippocampus dissociation, And in 225mm2Grown 10-12 days in the DMEM containing 10%FBS in culture flask.Lightly concussion and cultivate flask is so that godling Dissociated through spongiocyte, and the cell in the DMEM containing 10%FBS is repaved to be applied to 30,000 cells/wells and glued through PDL/ layers Even uncoated 48 are applied on 8 hole chamber slides of albumen coating for being imaged or being repaved with 100,000 cells/wells Determined on hole culture plate (3548, Corning) for cytohormone.The 4-5 hours after paving applies, cell is changed to serum-free In low glucose DMEM and keep overnight, then being handled with restructuring Tau and antibody.
Hippocampus-microglia cell coculture is by will be from 225mm2The microglia cell of culture flask dissociation Repave to be applied in 8 hole slide chambers and prepare that (each 12,500 mesoglias in hole are thin on 18DIV primary hippocampal neurons Born of the same parents and 25,000 neurons).4 hours after microglia cell paving applies, coculture is handled with restructuring Tau and antibody.
Recombinate the extracorporeal treatment of tau and antibody
For 18DIV hippocampal cultures or hippocampus-microglia cell coculture, by recombined human oligomerization at 37 DEG C Tau and antibody (with the respective 500nM of 1: 1 ratio) (come from 1: 1 18DIV hippocampal cultures to impinging upon neuronal culture：Newly Fresh NbActiv4 conditioned medium) in pre-incubation 1 hour, be then added in cell.Cell is mixed with tau antibody 72 hours (hippocampal cultures) are cultivated in thing or control in the medium together or (hippocampus-microglia cell was trained altogether in 48 hours Support thing).With PBS cell three times, it is then fixed.
For microglia cell culture, by recombined human oligomerization tau and antibody or control with each 125nM at 37 DEG C (immunocytochemistry/imaging) or each 250nM (cytohormone measure) pre-incubation 1 in the low glucose DMEM in the absence of serum Hour, then added in cell.For immunocytochemistry/imaging, cell is trained together with tau mixtures of antibodies or control 10min is educated, and, it is then fixed. with PBS three times.Determine for cytohormone, by cell and tau mixtures of antibodies or compare Cultivate 24 hours together, and the culture medium for collecting each hole determines for cytohormone.
Immunocytochemistry, imaging and quantization
Cell is fixed 15min with the PBS containing 4% paraformaldehyde, and permeated with the PBS of the X-100 containing 0.1%Triton 10min.Blocked using 10% donkey serum, and cell is cultivated together with the PBS containing primary antibody at 4 DEG C and stayed overnight, after And cultivated in for donkey together with the secondary antibody (Invitrogen) through Alexa fluorogens mark of caused appropriate material. Primary antibody used be anti-tau (DAKO), for develop across amino acid/11 1-24 RenTauNDuan areas rabbit against human T au, resist MAP2 (ab5392, Abcam) and anti-Iba-1 (ab5076, Abcam).With Prolong Gold DAPI (P36935, Invitrogen) and No. 1 cover glass installs slide.
It is confocal glimmering using the softwares of Zen 2010 (Carl Zeiss, Inc.) progress with LSM780 (Carl Zeiss, Inc.) Photoimaging.Imaging for hippocampal cultures and hippocampus-microglia cell coculture, uses Plan Apochromat 20 ×/0.8 0.98 μm of M27 object lens collection interval 5 z stack diagram pictures.Determined for MAP2 fragmentations, produce maximum intensity z Project and be used for image storehouse, and analyzed using Metamorph (Molecular Devices, Sunnyvale, CA).Use Median filter and closest deconvolution (deconvolution) are so that noise is reduced.Then made using neurite outgrowth module Neural process and cell body length are analyzed with morphological process.The fragment for being less than 15 pixels (6.225 μm) is grown relative to resultant signal Degree is standardized to obtain the measured value of MAP2 fragmentations.
Microglia cell is imaged with α-flat field apochromatism 100 ×/1.46M27 object lens.With Image J (1.43u, 64, NIH) carry out recombinating the quantization that tau absorbs in cell.Using Iba-1 signals as With reference to the ROI for artificially drawing cell compartment.The immunoreactive areas of tau and the integrated intensity for measuring ROI are relative to obtain In the tau immunoreactivities of area standardization.All analyses are carried out in the case where not knowing experiment condition.
As a result
The result of experiment is showed in Figure 13.As shown in FIG. 13A, the antibody with abundant effector function is not for god Protectiveness through the Tau toxicity in member-microglia cell coculture.Figure 13 B shows contact with oligomerization Tau and antibody The image (bottom diagram) of neuron-microglia cell coculture.Lack effector function antibody 37D3-H9 hIgG4 and Hu37D3-H9 hIgG1 (N297G) have the protectiveness for Tau toxicity, and 37D3-H9hIgG1 does not have.
Embodiment 10：Using Tau lesions in 37D3-H9 IgG2a or 37D3-H9 IgG2a DANG Tau Tg mouse Dose dependent is reduced
Turning for Thy1 promoter following table intelligent Tau P301L is maintained in C57BL/6N (Charles River) background DNA murine (Tau P301L-Tg).Tau P301L-Tg and wild type littermates are assigned in treatment group, and on every Mondays Secondary intraperitoneal (i.p.) gives 30mg/kg IgG2a controls (anti-gp120)；3rd, the anti-tau 37D3-H9WT of 10 or 30mg/kg IgG2a；3rd, the anti-tau 37D3-H9 DANG IgG2a of 10 or 30mg/kg.DANG refers to the D265A/N297G mutation in IgG2a, It eliminates effector function.With 10mg/ml concentration system in 10mM histidines (pH 5.8), 6% sucrose, 0.02%Tween 20 Standby all antibody administration solution.Treatment starts in 13 week old.Mouse group in In vivo study is male, and is staggeredly divided into 3 groups Group.In addition, collection does not carry out 3 TauP301L-Tg mouse of any processing to determine treating when originating at 3 monthly age Baseline lesions are horizontal.
In order to gather tissue, make mouse anesthesia (per 25g body weight 0.5ml) with 2.5% ethobrom, and through heart perfusion PBS.Collection brain and it is cut into two parts.Right hemisphere is fixed on continued overnight in 4% paraformaldehyde at 4 DEG C, is subsequently transferred to phosphorus In hydrochlorate buffered saline, then handled for immunohistochemistry.Left hemisphere is cut on ice it is smaller, then Freezing is for biochemical analysis at -80 DEG C.Afterbody intermediate plate is obtained from all mouse to confirm genotype.
UseBlock (NeuroScience Associates, Knoxville, TN), which doubles half brain, to be wrapped Bury into gelatin substrate, and tangential section is preced with 25 μ m thicks.It is in each piece, brain position is random relative to genotype and processing. As described previously to the brain of individual mice half orThe free floating section of block is dyed (Le Pichon etc. People, 2013, PLoS One, 8 (4)：E62342), cleaning replaces in Tris buffered salines cleaning and by primary but in the PBS Antibody is cultivated at 4 DEG C instead of cultivating at room temperature.Primary antibody is that (inside produces rabbit-anti pTau212/214；0.01μg/ ml).In order to avoid high background stainings, in the case of the mouse primary antibody of hypospecificity, we are special using corresponding hypotype Different in nature secondary antibody (such as biontnylated anti-mouse IgG3, Bethyl A90-111B).
Use Leica SCN400 (Leica Microsystems；Buffalo Grove, IL) full slide scanning system Immunohistochemical staining slide is imaged with 200 × magnifying power with the resolution ratio of 0.5 μm/pixel.In every animal 4 Target area (ROI) is artificially drawn in the hippocampus level matched somebody with somebody, and is measured in an automated manner using two end points described below Change the dyeing amount in these ROI.All graphical analyses are carried out in the case where not knowing dao gene type and treatment group.For IHC Quantitative positive pixel regional analysis is dyed, analyzes the digital picture (Le of the brain section through antibody labeling as described previously Pichon et al., 2013).By the way that total positive pixel is standardized to calculate pigmented section percentage relative to total ROI elemental areas. Only for positive pixel region, Beer Lambert law (Beer-Lambert law), absorbance=- log (transmitted light intensity are used Degree/incident intensity) calculate integrated intensity.
The result of the experiment is showed in Figure 14.Using anti-tau 37D3-H9 WT IgG2a or anti-tau 37D3-H9 DANG IgG2a cause the dose dependent of pTau212/214 in hippocampus to reduce.
Embodiment 11：The variants of humanization 37D3-H9 κ 1
Manufacture the humanized antibody based on the hu37D3-H9.v1 with the light chains of κ 1 and test its N28Stability.Test three The light chain variable district of kind variant and hu37D3-H9.v1 comparison are showed in Figure 18.Three kinds of variants in light chain variable district each other It is different：Hu37D3.v39 contains mutation F33L, and hu37D3.v40 contains mutation G29T, and hu37D3.v41 contains mutation N30Q.
Heat stress is carried out to antibody samples as follows.Sample Buffer is replaced by 20mM acetic acid histidines acetate, 240mM sugarcanes In sugared (pH 5.5), and it is diluted to 1mg/ml concentration.1ml samples are made to be subjected to that 2 weeks stress be continued at 40 DEG C, and second sample Product are stored at -70 DEG C as control.Digested with latter two sample using trypsase to produce peptide, liquid phase can be used Chromatography (LC)-mass spectrum (MS) analysis is analyzed the peptide.For each peptide in sample, the holdup time is obtained in MS (from LC) and high-resolution accurate mass and peptide ion fragmentation information (amino acid sequence information).In ± 10ppm window Under, according to data set, obtain the extraction chromatography of ions figure (XIC) of target peptide (peptide ion primary and through modification) and peak is carried out Integrate to determine area.By the way that (area of the peptide through modification) divided by (area of the peptide through modification adds the area of primary peptide) are multiplied The relative modification percentage of each sample is calculated with 100.Then in control (t=0) sample and stress be between (t=2 weeks) sample Compare these relative percentages.Shown percentage represent stress (t=2 weeks) value subtract control (t=0) value.As a result it is showed in table In 21.As a result prove that F33L mutation effectively reduce the desamidization in the humanization light chains of κ 1.
Stability of the table 21-hu37D3-H9.v1 variants in for stress the testing of desamidization.
At 25 DEG C kit and CM5 S family chips are caught using Biacore T200 instruments, GE Biacore people FAb Measure the affinity of humanized antibody variants.By antibody in HBSP (10mM HEPES (pH7.4), 150mM NaCl, 0.05% Tween 20) in be diluted to 1 μ g/ml, and caught 180 seconds under 10 μ l/min flow velocity.Using single cycle dynamic method and 30 μ l/min flow velocity is collected in HBSP with the dynamics data of people's Tau monomers of 1.2,3.7,11,33 and 100nM injections. The Tau monomers for injecting each concentration continue 3min period, and monitor dissociation and continue ten minutes.Between each circulation, with sequentially two Injection in one minute of secondary 10mM glycine (pH 2.1) makes surface regeneration.Data are fitted 1: 1 using BIAEvaluation softwares Binding model.Each antibody is analyzed twice in experiment；Data display in table 22 is average value ± scope.
Table 22：Affinity of the hu37D3-H9.v1 variants to monomer Tau
Embodiment 12：Hu37D3.v28.A4 hIgG4-S228P and hu37D3.v28.A4 hIgG4-S228P.YTE are being eaten Pharmacokinetics and pharmacodynamics in crab monkey
In order to assess hu37D3.v28.A4 hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE antibody Inside pharmacokinetics and pharmacodynamics, in the first phase with 50mg/kg dosage to five in every group conscious food crabs Monkey (machin (Macaca fascicularis)) applies single IV fast injections.Using anti-gD hIgG4 as control, its Used with 50mg/kg dosage.When being up to the Each point in time of 35 days upon administration, collect blood plasma and CSF samples are anti-to determine Tau antibody concentrations.After final sample collection, animal is recovered 63-64 days, then originate second stage.In second stage In, add another 3 animals to be divided into two groups 15 animals from the first stage；To first group of (n=9) administration of antibodies Hu37D3.v28.A4 hIgG4.S228P and resist to second group (n=9) using hu37D3.v28.A4 hIgG4-S228P.YTE Body (the two is with 50mg/kg).Upon administration the 2nd day and the 10th day when gather the brains of every group of 4 or 5 animals.
The antibody of human IgG 4 in machin blood plasma, CSF and brain homogenate (described below) is measured as follows with ELISA：Use Goat anti-human IgG monkeys adsorb antibody coating, and then addition originates in the plasma sample of 1: 100 dilution factor, originates in 1: 20 dilution The CSF samples of degree or the brain homogenate samples for originating in 1: 10 dilution factor, and end at addition through monkey adsorb for detection with The conjugated goat anti-human IgG antibodies of HRPO.Using 3,3 ', 5,5 '-tetramethyl benzidine develops the color, and uses 1M phosphoric acid Neutralize.Sample is read at 450/620nm.The standard curve range of the measure is 0.156-20ng/mL, and detect limit value for Blood plasma is 0.02 μ g/mL, is 0.003 μ g/mL for CSF, and is 0.002 μ g/mL for brain homogenate.Less than the result of this concentration Be reported as be less than can report value (LTR).
The result of pharmacokinetic analysis is showed in Figure 19 A (blood plasma) and 19B (CSF) and table 23 and 24.From the analysis Exclude the doubtful animal for treatment-resistant antibody positive (ATA+).These data displays, in hu37D3.v28.A4 YTE mutation are introduced in hIgG4.S228P Fc areas makes the periphery of antibody and CSF clearance rates slow down about twice.
Table 23：Average (± SD) plasma clearance and C after single IV Quick medicinesmaxEstimated value
Table 24：Average (± SD) CSF C after single IV Quick medicinesmaxEstimated value
Brain antibody concentration when the 2nd day and the 10th day after following measure injection.Brain tissue is weighed, and then containing There is cOmpleteTM, Mini, in the phosphate buffered saline (PBS) containing 1%NP-40 without EDTA protease inhibitor cocktail tablets Matter.Then the brain sample through homogenizing is rotated 1 hour at 4 DEG C, 20min is then rotated with 14,000rpm.Separate supernatant Liquid for as described above pass through ELISA carry out brain antibody measurement.The result of the experiment is showed in Figure 21 A-D.Antibody Concentration and antibody hu37D3.v28.A4 hIgG4-S228P.YTE of the hu37D3.v28.A4 hIgG4-S228P.YTE in brain Brain：Plasma concentration ratio is tended to be higher than antibody hu37D3.v28.A4 hIgG4.S228P.
Also measured were the pharmacodynamics reaction in blood plasma.Use electrochemical luminescence (ECL) immunoassays (Roche Professional Diagnostics (RPD), Penzberg, Germany) determine K2Total Tau concentration in edta plasma. Quantization to total Tau in people CSF is verifiedImmunoassays, and because of the similitude between people and machin Tau, willThe measurement that immunoassays are considered as to machin Tau in CSF and blood plasma is acceptable.It is unrelated with phosphorylation state, should Measure is caught and detection people and machin Tau amino acid/11 59-224 (area being present in all known isotypes).The measure Monitoring lower-cut (LDL) be 1.01pg/mL.Measure tolerance 15.0mg/mL hu37D3.v28.A4 hIgG4-S228P.YTE.
The result of pharmacodynamic analysis is showed in Figure 20.Excluding doubtful to lack baseline value for ATA+ animal and another Animal after, every group has 3 animals.Unexpectedly, in administration first day, in the animal handled with YTE variants, Blood plasma Tau levels are risen to than handling bigger degree with non-YTE variants.Further, since at earlier time points, between variant PK it is similar, therefore the result can not be predicted by pharmacokinetic reaction (Figure 20).Whole in the animal handled with YTE variants More sane reaction is kept in sampling duration.
Embodiment 13：Pharmacokinetics and drug effect of the hu37D3.v28.A4 hIgG4-S228P.YTE in machin brain Learn
In order to assess the antibody pharmacokinetics in brain, with 50mg/kg dosage to 12 conscious foods in every group Crab monkey (machin (Macaca fascicularis)) is fast using hu37D3.v28.A4 hIgG4-S228P.YTE single IV Speed injection.Using anti-gD hIgG4 as control, it is also used with 50mg/kg dosage.It is each up to 42 days upon administration During time point, plasma sample is collected to determine anti-Tau antibody concentrations.In addition, in the Each point in time of at most 42 days, 2 are killed Monkey, and determine brain and CSF antibody concentrations
Substantially antibody concentration is determined as described in embodiment 12.
Figure 22 A-B displayings are with machin brain during the Each point in time upon administration of logarithm (A) and linear (B) scale Antibody concentration.Table 25 shows brain concentration parameter.
Table 25：Average (± SD) brain PK parameter estimation values after single IV Quick medicines
Compared with anti-gD, hu37D3.v28.A4 hIgG4-S228P.YTE antibody shows that brain is dense at final time point Degree increase.
Also measured were the antibody concentration in Nao Ge areas (including hippocampus, cerebellum and volume cortex).Figure 23 A-C and table 26 to 28 are opened up Show the result of the analysis.
Table 26：Average hippocampus PK parameter estimation values after single IV Quick medicines
Table 27：Average cerebellum PK parameter estimation values after single IV Quick medicines
Table 28：Average amount cortex PK parameter estimation values after single IV Quick medicines
The result of the experiment is illustrated in after single IV injections is exposed to antibody hu37D3.v28.A4 by each area of brain In hIgG4-S228P.YTE.Entirety exposure in brain is suitable between the two groups, however, it is similar with the observed result in blood plasma, with Give anti-gD to compare, at final time point, give antibody hu37D3.v28.A4 hIgG4-S228P.YTE animals In, about twice of the antibody concentration increase in brain.Referring to Figure 23.These results indicate that after YTE antibody is given, protected in brain Hold more Gao Gu (final) concentration.
Also measured were the antibody concentration in the CSF and blood plasma changed over time.Figure 23 D (CSF) and 23E (blood plasma) and table 29 With 30 results for showing the analysis.
Table 29：Average CSF PK parameter estimation values after single IV Quick medicines
Table 30：Average blood plasma PK parameter estimation values after single IV Quick medicines
Again, it is similar with blood plasma and brain pharmacokinetics, compared with giving anti-gD, at final time point, giving In antibody hu37D3.v28.A4 hIgG4-S228P.YTE animal, about twice of the antibody concentration increase in CSF and blood plasma.Ginseng See Figure 23.
Using the plasma sample collected from machin, assess after single IV 50mg/kg administrations, antibody Hu37D3.v28.A4 hIgG4-S228P.YTE and control antibodies blood plasma pharmacodynamics.Use what is discussed in embodiment 12Immunoassays quantify to blood plasma Tau.
The result of pharmacodynamic analysis is showed in Figure 24 A-B.Figure 24 A show average total blood plasma relative to baseline criteria Tau concentration.Figure 24 B shows relative to indivedual monkeys in the research of baseline criteria total blood plasma Tau concentration.With being seen in embodiment 12 The result measured is similar, and administration of antibodies hu37D3.v28.A4 hIgG4-S228P.YTE cause the blood plasma Tau water dramatically increased It is flat.Although being not intended to be bound to any particular theory, these as shown by data hu37D3.v28.A4 hIgG4-S228P.YTE are combined Tau in brain, and therefore Tau is removed to periphery from brain.These results exist with hu37D3.v28.A4 hIgG4-S228P.YTE Target engagement in brain is consistent.
Although for clearness of understanding, foregoing hair has been described in considerable detail by means of explanation and embodiment It is bright, but illustrate to should not be construed as limiting the scope of the present invention with embodiment.All patents and scientific literature cited herein Disclosure is clearly incorporated in entirety by reference.
Sequence table
Sequence table
<110> AC IMMUNE SA
GENENTECH, INC.
ADOLFSSON, Oskar
AYALON, Gai
HOTZEL, Isidro
DICARA, Danielle
<120>Anti- TAU antibody and application method
<130> 01147-0006-00PCT
<140> PCT/US16/35409
<141> 2016-06-02
<150> US 62/171,693
<151> 2015-06-05
<160> 602
<170>PatentIn version 3s .5
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<223>Synthesis：37D3-H9 HVR-L3
<400> 17
Phe Gln Gly Ser Leu Val Pro Trp Thr
1 5
<210> 18
<400> 18
000
<210> 19
<400> 19
000
<210> 20
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：37D3-H9b weight chain variable districts (VH)
<400> 20
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Ala Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 21
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：37D3-H9b light chain variable districts (VL)
<400> 21
Glu Asp Leu Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 22
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：37D3-H9b HVR-H1
<400> 22
Ser Tyr Gly Met Ser
1 5
<210> 23
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：37D3-H9b HVR-H2
<400> 23
Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 24
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：37D3-H9b HVR-H3
<400> 24
Ser Tyr Ser Gly Ala Met Asp Tyr
1 5
<210> 25
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：37D3-H9b HVR-L1
<400> 25
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 26
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：37D3-H9b HVR-L2
<400> 26
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 27
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：37D3-H9b HVR-L3
<400> 27
Phe Gln Gly Ser Leu Val Pro Trp Thr
1 5
<210> 28
<400> 28
000
<210> 29
<400> 29
000
<210> 30
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：11E10-B8 weight chain variable districts (VH)
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Val Ser Tyr Asp Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 31
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：11E10-B8 light chain variable districts (VL)
<400> 31
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 32
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：11E10-B8 HVR-H1
<400> 32
Ser Tyr Gly Met Ser
1 5
<210> 33
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：11E10-B8 HVR-H2
<400> 33
Thr Ile Ser Gly Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 34
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：11E10-B8 HVR-H3
<400> 34
Ser Tyr Asp Gly Ala Met Asp Tyr
1 5
<210> 35
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：11E10-B8 HVR-L1
<400> 35
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 36
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：11E10-B8 HVR-L2
<400> 36
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 37
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：11E10-B8 HVR-L3
<400> 37
Phe Gln Gly Ser His Val Pro Trp Thr
1 5
<210> 38
<400> 38
000
<210> 39
<400> 39
000
<210> 40
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：54C1-H11 and 61E7-C4 weight chain variable districts (VH)
<400> 40
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Val Ser Cys Val Ala Ser Gly Phe Thr Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Asp Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Asn Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ser Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 41
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：54C1-H11 and 61E7-C4 light chain variable districts (VL)
<400> 41
Asp Thr Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 42
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：54C1-H11 and 61E7-C4 HVR-H1
<400> 42
Ser Tyr Gly Met Ser
1 5
<210> 43
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：54C1-H11 and 61E7-C4 HVR-H2
<400> 43
Thr Ile Ser Ser Gly Gly Asn Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 44
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：54C1-H11 and 61E7-C4 HVR-H3
<400> 44
Ser Tyr Ser Gly Ala Met Asp Tyr
1 5
<210> 45
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：54C1-H11 and 61E7-C4 HVR-L1
<400> 45
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 46
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：54C1-H11 and 61E7-C4 HVR-L2
<400> 46
Thr Val Ser Asn Arg Phe Ser
1 5
<210> 47
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：54C1-H11 and 61E7-C4 HVR-L3
<400> 47
Phe Gln Gly Ser His Val Pro Trp Thr
1 5
<210> 48
<400> 48
000
<210> 49
<400> 49
000
<210> 50
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：3A4-H4 weight chain variable districts (VH)
<400> 50
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Phe Cys
85 90 95
Ala Thr Ser Tyr Asp Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 51
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：3A4-H4 light chain variable districts (VL)
<400> 51
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Thr Leu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 52
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：3A4-H4 HVR-H1
<400> 52
Ser Tyr Gly Met Ser
1 5
<210> 53
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：3A4-H4 HVR-H2
<400> 53
Thr Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 54
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：3A4-H4 HVR-H3
<400> 54
Ser Tyr Asp Gly Ala Met Asp Tyr
1 5
<210> 55
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：3A4-H4 HVR-L1
<400> 55
Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 56
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：3A4-H4 HVR-L2
<400> 56
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 57
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：3A4-H4 HVR-L3
<400> 57
Phe Gln Gly Thr Leu Val Pro Trp Thr
1 5
<210> 58
<400> 58
000
<210> 59
<400> 59
000
<210> 60
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19H6-F7 weight chain variable districts (VH)
<400> 60
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Pro Ser Tyr Asp Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 61
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19H6-F7 light chain variable districts (VL)
<400> 61
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 62
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19H6-F7 HVR-H1
<400> 62
Ser Tyr Gly Met Ser
1 5
<210> 63
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19H6-F7 HVR-H2
<400> 63
Thr Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 64
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19H6-F7 HVR-H3
<400> 64
Ser Tyr Asp Gly Ala Met Asp Tyr
1 5
<210> 65
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19H6-F7 HVR-L1
<400> 65
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 66
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19H6-F7 HVR-L2
<400> 66
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 67
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19H6-F7 HVR-L3
<400> 67
Phe Gln Gly Ser Leu Val Pro Trp Thr
1 5
<210> 68
<400> 68
000
<210> 69
<400> 69
000
<210> 70
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：94B2-C1 weight chain variable districts (VH)
<400> 70
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile
35 40 45
Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Leu Ser Leu Thr Phe Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ala
<210> 71
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：94B2-C1 light chain variable districts (VL)
<400> 71
Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 72
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：94B2-C1 HVR-H1
<400> 72
Gly Tyr Thr Met Asn
1 5
<210> 73
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：94B2-C1 HVR-H2
<400> 73
Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 74
<211> 4
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：94B2-C1 HVR-H3
<400> 74
Gln Gly Ala Tyr
1
<210> 75
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：94B2-C1 HVR-L1
<400> 75
Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 76
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：94B2-C1 HVR-L2
<400> 76
Leu Val Ser Lys Leu Asp Ser
1 5
<210> 77
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：94B2-C1 HVR-L3
<400> 77
Trp Gln Gly Thr His Phe Pro Trp Thr
1 5
<210> 78
<400> 78
000
<210> 79
<400> 79
000
<210> 80
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：125B11-H3 weight chain variable districts (VH)
<400> 80
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Val Ala Ser Arg Phe Ile Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 81
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：125B11-H3 light chain variable districts (VL)
<400> 81
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Gly Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Asn Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Met Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Phe Arg Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 82
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：125B11-H3 HVR-H1
<400> 82
Asn Tyr Trp Met Asn
1 5
<210> 83
<211> 19
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：125B11-H3 HVR-H2
<400> 83
Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser
1 5 10 15
Val Lys Gly
<210> 84
<211> 4
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：125B11-H3 HVR-H3
<400> 84
Gly Thr Thr Tyr
1
<210> 85
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：125B11-H3 HVR-L1
<400> 85
Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala
1 5 10
<210> 86
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：125B11-H3 HVR-L2
<400> 86
Ser Ala Ser Ile Arg Tyr Thr
1 5
<210> 87
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：125B11-H3 HVR-L3
<400> 87
Gln Gln Phe Arg Thr Tyr Pro Tyr Thr
1 5
<210> 88
<400> 88
000
<210> 89
<400> 89
000
<210> 90
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：113F5-F7 weight chain variable districts (VH)
<400> 90
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Arg Leu Ser Cys Val Ala Ser Glu Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Ile Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ala Ser Asn Phe Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Ser Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 91
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：113F5-F7 light chain variable districts (VL)
<400> 91
Asp Ile Val Met Thr Gln Ser Gln Lys Ile Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Arg Pro Gly His Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ile Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Phe Ser Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Val Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 92
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：113F5-F7 HVR-H1
<400> 92
Asn Tyr Trp Met Asn
1 5
<210> 93
<211> 19
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：113F5-F7 HVR-H2
<400> 93
Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser
1 5 10 15
Val Lys Gly
<210> 94
<211> 4
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：113F5-F7 HVR-H3
<400> 94
Gly Thr Ser Tyr
1
<210> 95
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：113F5-F7 HVR-L1
<400> 95
Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala
1 5 10
<210> 96
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：113F5-F7 HVR-L2
<400> 96
Ser Ala Ser Arg Arg Phe Ser
1 5
<210> 97
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：113F5-F7 HVR-L3
<400> 97
Gln Gln Phe Ser Thr Tyr Pro Tyr Thr
1 5
<210> 98
<400> 98
000
<210> 99
<400> 99
000
<210> 100
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-B11 weight chain variable districts (VH)
<400> 100
Glu Val His Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Ser Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Phe Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Lys Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Ala Trp Arg Ala Arg Ala Thr Asn Ser Ala Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 101
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-B11 light chain variable districts (VL)
<400> 101
Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Arg Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 102
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-B11 HVR-H1
<400> 102
Asp Tyr Tyr Met Tyr
1 5
<210> 103
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-B11 HVR-H2
<400> 103
Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Phe Pro Lys Phe Gln
1 5 10 15
Gly
<210> 104
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-B11 HVR-H3
<400> 104
Trp Arg Ala Arg Ala Thr Asn Ser Ala Leu Asp Tyr
1 5 10
<210> 105
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-B11 HVR-L1
<400> 105
Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 106
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-B11 HVR-L2
<400> 106
Leu Val Ser Lys Leu Asp Ser
1 5
<210> 107
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-B11 HVR-L3
<400> 107
Trp Gln Gly Thr His Phe Pro Trp Thr
1 5
<210> 108
<400> 108
000
<210> 109
<400> 109
000
<210> 110
<211> 121
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-C8 weight chain variable districts (VH)
<400> 110
Glu Val His Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Ser Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Phe Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Lys Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Ala Trp Arg Ala Arg Ala Thr Asn Ser Ala Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 111
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-C8 light chain variable districts (VL)
<400> 111
Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Arg Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 112
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-C8 HVR-H1
<400> 112
Asp Tyr Tyr Met Tyr
1 5
<210> 113
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-C8 HVR-H2
<400> 113
Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Phe Pro Lys Phe Gln
1 5 10 15
Gly
<210> 114
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-C8 HVR-H3
<400> 114
Trp Arg Ala Arg Ala Thr Asn Ser Ala Leu Asp Tyr
1 5 10
<210> 115
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-C8 HVR-L1
<400> 115
Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 116
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-C8 HVR-L2
<400> 116
Leu Val Ser Lys Leu Asp Ser
1 5
<210> 117
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：26C1-C8 HVR-L3
<400> 117
Trp Gln Gly Thr His Phe Pro Trp Thr
1 5
<210> 118
<400> 118
000
<210> 119
<400> 119
000
<210> 120
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：30G1-B2 weight chain variable districts (VH)
<400> 120
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Glu Met Tyr Trp Val Lys Gln Thr Pro Val His Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ile Arg Gln Tyr Gly Asn Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 121
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：30G1-B2 light chain variable districts (VL)
<400> 121
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ala
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Phe Leu Gln Lys Pro Gly Leu Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Thr Arg Leu Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 122
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：30G1-B2 HVR-H1
<400> 122
Asp Tyr Glu Met Tyr
1 5
<210> 123
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：30G1-B2 HVR-H2
<400> 123
Ala Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 124
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：30G1-B2 HVR-H3
<400> 124
Gln Tyr Gly Asn Trp Phe Pro Tyr
1 5
<210> 125
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：30G1-B2 HVR-L1
<400> 125
Arg Ser Ser Gln Ser Leu Val His Ala Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 126
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：30G1-B2 HVR-L2
<400> 126
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 127
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：30G1-B2 HVR-L3
<400> 127
Ser Gln Ser Thr His Val Pro Phe Thr
1 5
<210> 128
<400> 128
000
<210> 129
<400> 129
000
<210> 130
<211> 114
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：66F5-A1 weight chain variable districts (VH)
<400> 130
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Asp Tyr
20 25 30
Glu Met Asn Trp Val Lys Gln Thr Pro Val His Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Asp Pro Glu Asn Gly Gly Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Ile Val Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ser Gly Pro His Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
100 105 110
Ser Ser
<210> 131
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：66F5-A1 light chain variable districts (VL)
<400> 131
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Met Ser Val Gly
1 5 10 15
Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln
85 90 95
His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 132
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：66F5-A1 HVR-H1
<400> 132
Asp Tyr Glu Met Asn
1 5
<210> 133
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：66F5-A1 HVR-H2
<400> 133
Ala Ile Asp Pro Glu Asn Gly Gly Thr Ala Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 134
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：66F5-A1 HVR-H3
<400> 134
Pro His Phe Asp Tyr
1 5
<210> 135
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：66F5-A1 HVR-L1
<400> 135
Lys Ser Ser Gln Ser Leu Leu Asn Ser Ser Thr Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 136
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：66F5-A1 HVR-L2
<400> 136
Phe Ala Ser Thr Arg Glu Ser
1 5
<210> 137
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：66F5-A1 HVR-L3
<400> 137
Gln Gln His Tyr Ser Thr Pro Tyr Thr
1 5
<210> 138
<400> 138
000
<210> 139
<400> 139
000
<210> 140
<211> 119
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：123E9-A1 weight chain variable districts (VH)
<400> 140
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Pro Asn Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ala Gly Phe Gly Asp Ser Phe Ser Phe Trp Gly Leu Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 141
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：123E9-A1 light chain variable districts (VL)
<400> 141
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Phe Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 142
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：123E9-A1 HVR-H1
<400> 142
Asp Tyr Tyr Met Lys
1 5
<210> 143
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：123E9-A1 HVR-H2
<400> 143
Asp Ile Asp Pro Asn Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 144
<211> 10
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：123E9-A1 HVR-H3
<400> 144
Ser Ala Gly Phe Gly Asp Ser Phe Ser Phe
1 5 10
<210> 145
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：123E9-A1 HVR-L1
<400> 145
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 146
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：123E9-A1 HVR-L2
<400> 146
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 147
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：123E9-A1 HVR-L3
<400> 147
Phe Gln Gly Ser His Val Pro Pro Thr
1 5
<210> 148
<400> 148
000
<210> 149
<400> 149
000
<210> 150
<211> 119
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：15C6-A7 weight chain variable districts (VH)
<400> 150
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Met Met Thr Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Lys Trp Val Lys Gln Ser Asn Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Leu Asp Pro Tyr Thr Gly Gly Ala Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met His Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Arg Gly Tyr Gly Asp Ser Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 151
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：15C6-A7 light chain variable districts (VL)
<400> 151
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Phe Gln Gly
85 90 95
Ser His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 152
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：15C6-A7 HVR-H1
<400> 152
Asp Tyr Tyr Met Lys
1 5
<210> 153
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：15C6-A7 HVR-H2
<400> 153
Asp Leu Asp Pro Tyr Thr Gly Gly Ala Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 154
<211> 10
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：15C6-A7 HVR-H3
<400> 154
Ser Arg Gly Tyr Gly Asp Ser Phe Ala Tyr
1 5 10
<210> 155
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：15C6-A7 HVR-L1
<400> 155
Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 156
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：15C6-A7 HVR-L2
<400> 156
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 157
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：15C6-A7 HVR-L3
<400> 157
Phe Gln Gly Ser His Val Pro Pro Thr
1 5
<210> 158
<400> 158
000
<210> 159
<400> 159
000
<210> 160
<211> 119
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19F8-B1 weight chain variable districts (VH)
<400> 160
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Leu Asn Pro Asn Asn Gly Gly Thr Leu Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Gln Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Phe Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ala Gly Tyr Gly Asp Ser Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 161
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19F8-B1 light chain variable districts (VL)
<400> 161
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Phe Cys Phe Gln Gly
85 90 95
Ser His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 162
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19F8-B1 HVR-H1
<400> 162
Asp Tyr Tyr Met Lys
1 5
<210> 163
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19F8-B1 HVR-H2
<400> 163
Asp Leu Asn Pro Asn Asn Gly Gly Thr Leu Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 164
<211> 10
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19F8-B1 HVR-H3
<400> 164
Ser Ala Gly Tyr Gly Asp Ser Phe Ala Tyr
1 5 10
<210> 165
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19F8-B1 HVR-L1
<400> 165
Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 166
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19F8-B1 HVR-L2
<400> 166
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 167
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：19F8-B1 HVR-L3
<400> 167
Phe Gln Gly Ser His Val Pro Pro Thr
1 5
<210> 168
<400> 168
000
<210> 169
<400> 169
000
<210> 170
<211> 119
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：24A11-D5 weight chain variable districts (VH)
<400> 170
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Leu Asn Pro Lys Asn Gly Gly Ile Ile Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Gln Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Phe Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Gly Asp Ser Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 171
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：24A11-D5 light chain variable districts (VL)
<400> 171
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Phe Cys Phe Gln Gly
85 90 95
Ser His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 172
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：24A11-D5 HVR-H1
<400> 172
Asp Tyr Tyr Met Lys
1 5
<210> 173
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：24A11-D5 HVR-H2
<400> 173
Asp Leu Asn Pro Lys Asn Gly Gly Ile Ile Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 174
<211> 10
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：24A11-D5 HVR-H3
<400> 174
Ser Gly Gly Tyr Gly Asp Ser Phe Ala Tyr
1 5 10
<210> 175
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：24A11-D5 HVR-L1
<400> 175
Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 176
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：24A11-D5 HVR-L2
<400> 176
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 177
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：24A11-D5 HVR-L3
<400> 177
Phe Gln Gly Ser His Val Pro Pro Thr
1 5
<210> 178
<400> 178
000
<210> 179
<400> 179
000
<210> 180
<211> 114
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：126F11-G11 weight chain variable districts (VH)
<400> 180
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Ser Lys Phe
50 55 60
Gln Gly Lys Ala Thr Ile Thr Thr Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Leu Asp Phe Ala Tyr Gly Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
100 105 110
Ser Ser
<210> 181
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：126F11-G11 light chain variable districts (VL)
<400> 181
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Pro Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 182
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：126F11-G11 HVR-H1
<400> 182
Asp Asp Tyr Met His
1 5
<210> 183
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：126F11-G11 HVR-H2
<400> 183
Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Ser Lys Phe Gln
1 5 10 15
Gly
<210> 184
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：126F11-G11 HVR-H3
<400> 184
Phe Ala Tyr Gly Tyr
1 5
<210> 185
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：126F11-G11 HVR-L1
<400> 185
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 186
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：126F11-G11 HVR-L2
<400> 186
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 187
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：126F11-G11 HVR-L3
<400> 187
Phe Gln Gly Ser His Val Pro Pro Ala
1 5
<210> 188
<400> 188
000
<210> 189
<400> 189
000
<210> 190
<211> 120
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：89F4-A1 weight chain variable districts (VH)
<400> 190
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ala Tyr Phe Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Thr Met
65 70 75 80
Leu Tyr Leu Gln Met Asn Asn Leu Lys Ser Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Ser Gly Gly Asn Tyr Val Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 191
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：89F4-A1 light chain variable districts (VL)
<400> 191
Asn Ile Met Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Phe Tyr Ser
20 25 30
Ser Glu Gln Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Gly Glu Asp Leu Ala Val Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 192
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：89F4-A1 HVR-H1
<400> 192
Thr Tyr Ala Met Asn
1 5
<210> 193
<211> 19
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：89F4-A1 HVR-H2
<400> 193
Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ala Tyr Phe Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 194
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：89F4-A1 HVR-H3
<400> 194
Gly Gly Asn Tyr Val Pro Phe Ala Tyr
1 5
<210> 195
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：89F4-A1 HVR-L1
<400> 195
Lys Ser Ser Gln Ser Val Phe Tyr Ser Ser Glu Gln Arg Asn Tyr Leu
1 5 10 15
Ala
<210> 196
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：89F4-A1 HVR-L2
<400> 196
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 197
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：89F4-A1 HVR-L3
<400> 197
His Gln Tyr Leu Ser Ser Phe Thr
1 5
<210> 198
<400> 198
000
<210> 199
<400> 199
000
<210> 200
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：93A8-D2 weight chain variable districts (VH)
<400> 200
Glu Val Gln Leu Gln Gln Ser Gly Pro Val Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Val Asn Trp Val Lys Gln Ser His Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Asn Pro Asn Asn Gly Arg Thr Ser Tyr Asn Gln Asn Phe
50 55 60
Asn Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Phe
65 70 75 80
Met Asp Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Glu Gly Gly Thr Gly Tyr Trp Gly Gln Gly Thr Thr Leu Ser
100 105 110
Val Ser Ser
115
<210> 201
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：93A8-D2 light chain variable districts (VL)
<400> 201
Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Ala Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 202
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：93A8-D2 HVR-H1
<400> 202
Asp Tyr Tyr Val Asn
1 5
<210> 203
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：93A8-D2 HVR-H2
<400> 203
Leu Ile Asn Pro Asn Asn Gly Arg Thr Ser Tyr Asn Gln Asn Phe Asn
1 5 10 15
Asp
<210> 204
<211> 6
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：93A8-D2 HVR-H3
<400> 204
Glu Gly Gly Thr Gly Tyr
1 5
<210> 205
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：93A8-D2 HVR-L1
<400> 205
Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 206
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：93A8-D2 HVR-L2
<400> 206
Leu Val Ser Lys Leu Asp Ser
1 5
<210> 207
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：93A8-D2 HVR-L3
<400> 207
Trp Gln Gly Thr His Phe Pro Arg Thr
1 5
<210> 208
<400> 208
000
<210> 209
<400> 209
000
<210> 210
<211> 120
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：14F5-D9 weight chain variable districts (VH)
<400> 210
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Asp Phe
20 25 30
Tyr Met Glu Trp Val Arg Gln Ser Pro Gly Lys Arg Leu Glu Trp Ile
35 40 45
Ala Ala Ser Lys Asn Lys Ala Asn Asp Tyr Thr Thr Glu Tyr Asn Ala
50 55 60
Ser Val Lys Asp Arg Phe Phe Val Ser Arg Asp Thr Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ala Leu Arg Ala Glu Asp Thr Ala Ile Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Leu Gly Thr Val Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 211
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：14F5-D9 light chain variable districts (VL)
<400> 211
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Phe Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr Leu Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 212
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：14F5-D9 HVR-H1
<400> 212
Asp Phe Tyr Met Glu
1 5
<210> 213
<211> 19
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：14F5-D9 HVR-H2
<400> 213
Ala Ser Lys Asn Lys Ala Asn Asp Tyr Thr Thr Glu Tyr Asn Ala Ser
1 5 10 15
Val Lys Asp
<210> 214
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：14F5-D9 HVR-H3
<400> 214
Asp Ala Leu Gly Thr Val Phe Ala Tyr
1 5
<210> 215
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：14F5-D9 HVR-L1
<400> 215
Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 216
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：14F5-D9 HVR-L2
<400> 216
Lys Val Phe Asn Arg Phe Ser
1 5
<210> 217
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：14F5-D9 HVR-L3
<400> 217
Ser Gln Ser Thr Leu Val Pro Leu Thr
1 5
<210> 218
<400> 218
000
<210> 219
<400> 219
000
<210> 220
<211> 122
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：73H6-B8 weight chain variable districts (VH)
<400> 220
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Ile Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Val Val Ile Trp Ser Asp Gly Ser Thr Thr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Gln Gly Gly Phe Ile Thr Thr Ala Tyr Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 221
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：73H6-B8 light chain variable districts (VL)
<400> 221
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 222
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：73H6-B8 HVR-H1
<400> 222
Ser Tyr Gly Val His
1 5
<210> 223
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：73H6-B8 HVR-H2
<400> 223
Val Ile Trp Ser Asp Gly Ser Thr Thr Tyr Asn Ser Ala Leu Lys Ser
1 5 10 15
<210> 224
<211> 14
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：73H6-B8 HVR-H3
<400> 224
Gln Gly Gly Phe Ile Thr Thr Ala Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 225
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：73H6-B8 HVR-L1
<400> 225
Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 226
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：73H6-B8 HVR-L2
<400> 226
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 227
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：73H6-B8 HVR-L3
<400> 227
Lys Gln Ser Tyr Asn Leu Tyr Thr
1 5
<210> 228
<400> 228
000
<210> 229
<400> 229
000
<210> 230
<211> 120
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：22G7-C9 weight chain variable districts (VH)
<400> 230
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Cys
20 25 30
Ser Ile His Trp Val Lys Gln Ala Pro Gly Glu Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Ser Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Phe
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Ser Glu Asp Thr Ala Ser Tyr Phe Cys
85 90 95
Gly Thr Ala Tyr Tyr Arg Tyr Asp Gly Ala Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 231
<211> 111
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：22G7-C9 light chain variable districts (VL)
<400> 231
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Tyr Ser Tyr Met His Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 232
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：22G7-C9 HVR-H1
<400> 232
Asp Cys Ser Ile His
1 5
<210> 233
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：22G7-C9 HVR-H2
<400> 233
Trp Ile Asn Thr Glu Thr Gly Glu Pro Ser Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 234
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：22G7-C9 HVR-H3
<400> 234
Ala Tyr Tyr Arg Tyr Asp Gly Ala Leu Asp Tyr
1 5 10
<210> 235
<211> 15
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：22G7-C9 HVR-L1
<400> 235
Arg Ala Ser Gln Ser Val Ser Thr Ser Ser Tyr Ser Tyr Met His
1 5 10 15
<210> 236
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：22G7-C9 HVR-L2
<400> 236
Tyr Ala Ser Asn Leu Glu Ser
1 5
<210> 237
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：22G7-C9 HVR-L3
<400> 237
Gln His Ser Trp Glu Leu Pro Trp Thr
1 5
<210> 238
<400> 238
000
<210> 239
<400> 239
000
<210> 240
<211> 116
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：7A11-C12 weight chain variable districts (VH)
<400> 240
Gln Ile Gln Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asp Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Thr Val Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 241
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：7A11-C12 light chain variable districts (VL)
<400> 241
Asp Val Val Met Ser Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp His Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Ile Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 242
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：7A11-C12 HVR-H1
<400> 242
Asn Tyr Gly Met Asn
1 5
<210> 243
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：7A11-C12 HVR-H2
<400> 243
Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe Lys
1 5 10 15
Gly
<210> 244
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：7A11-C12 HVR-H3
<400> 244
Gly Thr Val Ser Phe Pro Tyr
1 5
<210> 245
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：7A11-C12 HVR-L1
<400> 245
Arg Ser Ser Gln Asn Leu Val His Ser Asp Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 246
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：7A11-C12 HVR-L2
<400> 246
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 247
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：7A11-C12 HVR-L3
<400> 247
Ser Gln Ser Thr His Val Ile Phe Thr
1 5
<210> 248
<400> 248
000
<210> 249
<400> 249
000
<210> 250
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：12A10-E8 weight chain variable districts (VH)
<400> 250
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Met Tyr Thr Gly Glu Pro Thr Tyr Gly Asp Asp Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Glu Thr Ser Val Ser Thr Val Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Lys Glu Asp Thr Ala Thr Phe Phe Cys
85 90 95
Ala Arg Gly Gly Arg Pro Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 251
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：12A10-E8 light chain variable districts (VL)
<400> 251
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Phe Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Leu Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 252
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：12A10-E8 HVR-H1
<400> 252
Asn Tyr Gly Met Asn
1 5
<210> 253
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：12A10-E8 HVR-H2
<400> 253
Trp Ile Asn Met Tyr Thr Gly Glu Pro Thr Tyr Gly Asp Asp Phe Lys
1 5 10 15
Gly
<210> 254
<211> 6
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：12A10-E8 HVR-H3
<400> 254
Gly Gly Arg Pro Asp Tyr
1 5
<210> 255
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：12A10-E8 HVR-L1
<400> 255
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 256
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：1 2A10-E8 HVR-L2
<400> 256
Lys Val Phe Asn Arg Phe Ser
1 5
<210> 257
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：12A10-E8 HVR-L3
<400> 257
Leu Gln Gly Ser His Val Pro Tyr Thr
1 5
<210> 258
<400> 258
000
<210> 259
<400> 259
000
<210> 260
<211> 120
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：55E7-F11 weight chain variable districts (VH)
<400> 260
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Ala Gly Tyr Phe Tyr Gly Gly Tyr Phe Asp Val Trp Gly Thr
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 261
<211> 108
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：55E7-F11 light chain variable districts (VL)
<400> 261
Glu Leu Val Leu Thr Gln Ser Pro Thr Thr Met Ala Ala Ser Pro Gly
1 5 10 15
Lys Lys Ile Thr Ile Thr Cys Ser Ala Ser Ser Ser Ile Ser Ser Asn
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Phe Ser Pro Lys Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Gly Thr Met Glu
65 70 75 80
Ala Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Gly Ser Ser Leu Pro
85 90 95
Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 262
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：55E7-F11 HVR-H1
<400> 262
Asn Tyr Trp Met Asn
1 5
<210> 263
<211> 19
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：55E7-F11 HVR-H2
<400> 263
Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser
1 5 10 15
Val Lys Gly
<210> 264
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：55E7-F11 HVR-H3
<400> 264
Tyr Phe Tyr Gly Gly Tyr Phe Asp Val
1 5
<210> 265
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：55E7-F11 HVR-L1
<400> 265
Ser Ala Ser Ser Ser Ile Ser Ser Asn Tyr Leu His
1 5 10
<210> 266
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：55E7-F11 HVR-L2
<400> 266
Arg Thr Ser Asn Leu Ala Ser
1 5
<210> 267
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：55E7-F11 HVR-L3
<400> 267
Gln Gln Gly Ser Ser Leu Pro Phe Thr
1 5
<210> 268
<400> 268
000
<210> 269
<400> 269
000
<210> 270
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：52F6-F11 weight chain variable districts (VH)
<400> 270
Gln Val Gln Leu Gln Gln Ser Gly Thr Glu Leu Ala Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr His Tyr
20 25 30
Trp Met His Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Thr Asn Asp Tyr Thr Lys Tyr Asn Gln Asn Phe
50 55 60
Arg Asp Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Asn Ser Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Tyr Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Gly Asn Arg Val Phe Asp Phe Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 271
<211> 109
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：52F6-F11 light chain variable districts (VL)
<400> 271
Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Phe Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala
65 70 75 80
Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 272
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：52F6-F11 HVR-H1
<400> 272
His Tyr Trp Met His
1 5
<210> 273
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：52F6-F11 HVR-H2
<400> 273
Tyr Ile Tyr Pro Thr Asn Asp Tyr Thr Lys Tyr Asn Gln Asn Phe Arg
1 5 10 15
Asp
<210> 274
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：52F6-F11 HVR-H3
<400> 274
Ala Gly Asn Arg Val Phe Asp Phe
1 5
<210> 275
<211> 14
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：52F6-F11 HVR-L1
<400> 275
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Phe Ala Asn
1 5 10
<210> 276
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：52F6-F11 HVR-L2
<400> 276
Gly Thr Asn Asn Arg Ala Pro
1 5
<210> 277
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：52F6-F11 HVR-L3
<400> 277
Ala Leu Trp Tyr Ser Asn Leu Trp Val
1 5
<210> 278
<400> 278
000
<210> 279
<400> 279
000
<210> 280
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 weight chain variable districts (VH)
<400> 280
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 281
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 light chain variable districts (VL)
<400> 281
Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 282
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 HVR-H1
<400> 282
Ser Tyr Gly Met Ser
1 5
<210> 283
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 HVR-H2
<400> 283
Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 284
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 HVR-H3
<400> 284
Ser Tyr Ser Gly Ala Met Asp Tyr
1 5
<210> 285
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 HVR-L1
<400> 285
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 286
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 HVR-L2
<400> 286
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 287
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 HVR-L3
<400> 287
Phe Gln Gly Ser Leu Val Pro Trp Thr
1 5
<210> 288
<211> 447
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 IgG1 heavy chains
<400> 288
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 289
<211> 219
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 IgG1 light chains
<400> 289
Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 290
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5 weight chain variable districts (VH)
<400> 290
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 291
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5 light chain variable districts (VL)
<400> 291
Glu Asp Val Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 292
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5 HVR-H1
<400> 292
Ser Tyr Gly Met Ser
1 5
<210> 293
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5 HVR-H2
<400> 293
Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 294
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5 HVR-H3
<400> 294
Ser Tyr Ser Gly Ala Met Asp Tyr
1 5
<210> 295
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5 HVR-L1
<400> 295
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 296
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5 HVR-L2
<400> 296
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 297
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5 HVR-L3
<400> 297
Phe Gln Gly Ser Leu Val Pro Trp Thr
1 5
<210> 298
<400> 298
000
<210> 299
<400> 299
000
<210> 300
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.v105 weight chain variable districts (VH)
<400> 300
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 301
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.v105 light chain variable districts (VL)
<400> 301
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 302
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.v105 HVR-H1
<400> 302
Gly Tyr Thr Met Asn
1 5
<210> 303
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.v105 HVR-H2
<400> 303
Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 304
<211> 4
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.v105 HVR-H3
<400> 304
Gln Gly Ala Tyr
1
<210> 305
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.v105 HVR-L1
<400> 305
Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 306
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.v105 HVR-L2
<400> 306
Leu Val Ser Lys Leu Asp Ser
1 5
<210> 307
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.v105 HVR-L3
<400> 307
Trp Gln Gly Thr His Phe Pro Trp Thr
1 5
<210> 308
<400> 308
000
<210> 309
<400> 309
000
<210> 310
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu125B11.v17 weight chain variable districts (VH)
<400> 310
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 311
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu125B11.v17 light chain variable districts (VH)
<400> 311
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Arg Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 312
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v17 HVR-H1
<400> 312
Asn Tyr Trp Met Asn
1 5
<210> 313
<211> 19
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v17 HVR-H2
<400> 313
Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser
1 5 10 15
Val Lys Gly
<210> 314
<211> 4
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v17 HVR-H3
<400> 314
Gly Thr Thr Tyr
1
<210> 315
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v17 HVR-L1
<400> 315
Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala
1 5 10
<210> 316
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v17 HVR-L2
<400> 316
Ser Ala Ser Ile Arg Tyr Thr
1 5
<210> 317
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v17 HVR-L3
<400> 317
Gln Gln Phe Arg Thr Tyr Pro Tyr Thr
1 5
<210> 318
<400> 318
000
<210> 319
<400> 319
000
<210> 320
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu125B11.v26 weight chain variable districts (VH)
<400> 320
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 321
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu125B11.v26 light chain variable districts (VH)
<400> 321
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Arg Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 322
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v26 HVR-H1
<400> 322
Asn Tyr Trp Met Asn
1 5
<210> 323
<211> 19
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v26 HVR-H2
<400> 323
Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser
1 5 10 15
Val Lys Gly
<210> 324
<211> 4
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v26 HVR-H3
<400> 324
Gly Thr Thr Tyr
1
<210> 325
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v26 HVR-L1
<400> 325
Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala
1 5 10
<210> 326
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v26 HVR-L2
<400> 326
Ser Ala Ser Ile Arg Tyr Thr
1 5
<210> 327
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v26 HVR-L3
<400> 327
Gln Gln Phe Arg Thr Tyr Pro Tyr Thr
1 5
<210> 328
<400> 328
000
<210> 329
<400> 329
000
<210> 330
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu125B11.v28 weight chain variable districts (VH)
<400> 330
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 331
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu125B11.v28 light chain variable districts (VH)
<400> 331
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Arg Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 332
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v28 HVR-H1
<400> 332
Asn Tyr Trp Met Asn
1 5
<210> 333
<211> 19
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v28 HVR-H2
<400> 333
Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser
1 5 10 15
Val Lys Gly
<210> 334
<211> 4
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v28 HVR-H3
<400> 334
Gly Thr Thr Tyr
1
<210> 335
<211> 11
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v28 HVR-L1
<400> 335
Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala
1 5 10
<210> 336
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v28 HVR-L2
<400> 336
Ser Ala Ser Ile Arg Tyr Thr
1 5
<210> 337
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11.v28 HVR-L3
<400> 337
Gln Gln Phe Arg Thr Tyr Pro Tyr Thr
1 5
<210> 338
<400> 338
000
<210> 339
<400> 339
000
<210> 340
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 weight chain variable districts (VH)
<400> 340
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 341
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 light chain variable districts (VL)
<400> 341
Asp Asp Val Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 342
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 HVR-H1
<400> 342
Ser Tyr Gly Met Ser
1 5
<210> 343
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 HVR-H2
<400> 343
Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 344
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 HVR-H3
<400> 344
Ser Tyr Ser Gly Ala Met Asp Tyr
1 5
<210> 345
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 HVR-L1
<400> 345
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 346
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 HVR-L2
<400> 346
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 347
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 HVR-L3
<400> 347
Phe Gln Gly Ser Leu Val Pro Trp Thr
1 5
<210> 348
<211> 444
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 IgG4-S228P.YTE heavy chains
<400> 348
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 349
<211> 219
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 IgG4-S228P.YTE light chains
<400> 349
Asp Asp Val Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 350
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：It stress not compare (average value, n=9)
<400> 350
Glu Asp Leu His Ser Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 351
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5
<400> 351
Glu Asp Leu His Ser Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 352
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.1
<400> 352
Glu Asp Leu His Ser Asn Ala Asn Thr Tyr Phe Leu
1 5 10
<210> 353
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.2
<400> 353
Glu Asp Leu His Ser Ser Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 354
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.3
<400> 354
Glu Asp Leu His Ser Asp Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 355
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.4
<400> 355
Glu Asp Leu His Ser Gln Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 356
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.5
<400> 356
Glu Asp Leu His Ser Glu Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 357
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.6
<400> 357
Glu Asp Leu His Ser Ala Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 358
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.7
<400> 358
Glu Asp Leu His Ser Asn Gly Asp Thr Tyr Phe Leu
1 5 10
<210> 359
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.8
<400> 359
Glu Asp Leu His Ser Asn Gly Gln Thr Tyr Phe Leu
1 5 10
<210> 360
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.9
<400> 360
Glu Asp Leu His Ser Asn Gly Glu Thr Tyr Phe Leu
1 5 10
<210> 361
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.10
<400> 361
Glu Asp Leu His Ser Asn Gly Ala Thr Tyr Phe Leu
1 5 10
<210> 362
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v5.11
<400> 362
Glu Asp Leu His Ser Asn Gly Ser Thr Tyr Phe Leu
1 5 10
<210> 363
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28
<400> 363
Asp Asp Leu His Ser Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 364
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A2
<400> 364
Asp Asp Leu His Ser Asn Gly Asn Thr Tyr Phe His
1 5 10
<210> 365
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A4
<400> 365
Asp Asp Leu His Ser Asn Gly Asn Thr Tyr Leu Leu
1 5 10
<210> 366
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A6
<400> 366
Asp Asp Leu His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10
<210> 367
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A8
<400> 367
Asp Asp Met His Ser Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 368
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A10
<400> 368
Asp Asp Met His Ser Asn Gly Asn Thr Tyr Phe His
1 5 10
<210> 369
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A12
<400> 369
Asp Asp Met His Ser Asn Gly Asn Thr Tyr Leu Leu
1 5 10
<210> 370
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A14
<400> 370
Asp Asp Met His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10
<210> 371
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A16
<400> 371
Asp Val Leu His Ser Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 372
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A18
<400> 372
Asp Val Leu His Ser Asn Gly Asn Thr Tyr Phe His
1 5 10
<210> 373
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A20
<400> 373
Asp Val Leu His Ser Asn Gly Asn Thr Tyr Leu Leu
1 5 10
<210> 374
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A22
<400> 374
Asp Val Leu His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10
<210> 375
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A24
<400> 375
Asp Val Met His Ser Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 376
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A26
<400> 376
Asp Val Met His Ser Asn Gly Asn Thr Tyr Phe His
1 5 10
<210> 377
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A28
<400> 377
Asp Val Met His Ser Asn Gly Asn Thr Tyr Leu Leu
1 5 10
<210> 378
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.A30
<400> 378
Asp Val Met His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10
<210> 379
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.B1
<400> 379
Asp Asp Leu His Ser Ile Gly Asn Thr Phe Phe Leu
1 5 10
<210> 380
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.B2
<400> 380
Asp Asp Leu His Ser Met Gly Asn Thr Phe Phe Leu
1 5 10
<210> 381
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.B3
<400> 381
Asp Asp Leu His Ser Gln Gly Asn Thr Trp Phe Leu
1 5 10
<210> 382
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.B4
<400> 382
Asp Asp Leu His Ser Gln Gly Asn Thr His Phe Leu
1 5 10
<210> 383
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.B6
<400> 383
Asp Asp Leu His Ser Asp Gly Asn Thr Arg Phe Leu
1 5 10
<210> 384
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.B7
<400> 384
Asp Asp Leu His Ser Asp Gly Asn Thr Lys Phe Leu
1 5 10
<210> 385
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.B8
<400> 385
Asp Asp Leu His Ser Glu Gly Asn Thr Arg Phe Leu
1 5 10
<210> 386
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.C1
<400> 386
Asp Asp Leu His Ser Asn Asn Asn Thr Tyr Phe Leu
1 5 10
<210> 387
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.C2
<400> 387
Asp Asp Leu His Ser Asn Asp Asn Thr Tyr Phe Leu
1 5 10
<210> 388
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.D1
<400> 388
Asp Asp Leu His Ala Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 389
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：It stress not compare (average value, n=9)
<400> 389
Glu Asp Leu His Ser Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 390
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.E1
<400> 390
Asp Asp Leu Asn Ser Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 391
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.E2
<400> 391
Asp Asp Leu Gln Ser Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 392
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.E3
<400> 392
Asp Asp Leu Asp Ser Asp Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 393
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.F1
<400> 393
Asp Asp Leu His Ser Asn Thr Asn Thr Tyr Phe Leu
1 5 10
<210> 394
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.F2
<400> 394
Asp Asp Leu His Thr Asn Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 395
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.F3
<400> 395
Asp Asp Leu His Thr Asn Ala Asn Thr Tyr Phe Leu
1 5 10
<210> 396
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.51
<400> 396
Glu Asp Leu His Ser His Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 397
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.52
<400> 397
Glu Asp Leu His Ser Lys Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 398
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.53
<400> 398
Glu Asp Leu His Ser Arg Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 399
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.54
<400> 399
Glu Asp Leu His Ser Leu Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 400
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.55
<400> 400
Asp Asp Leu His Ser Asn Gln Asn Thr Tyr Phe Leu
1 5 10
<210> 401
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.56
<400> 401
Asp Asp Leu His Ser Asn Tyr Asn Thr Tyr Phe Leu
1 5 10
<210> 402
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v28.57
<400> 402
Asp Asp Leu His Ser Asn Phe Asn Thr Tyr Phe Leu
1 5 10
<210> 403
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.1
<400> 403
Glu Asp Leu His Ser Asn Gly Asp Thr Tyr Phe Leu
1 5 10
<210> 404
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.2
<400> 404
Glu Asp Leu His Ser Asn Gly Gln Thr Tyr Phe Leu
1 5 10
<210> 405
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.3
<400> 405
Glu Asp Leu His Ser Asn Gly Glu Thr Tyr Phe Leu
1 5 10
<210> 406
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.4
<400> 406
Glu Asp Leu His Ser Asn Gly Ala Thr Tyr Phe Leu
1 5 10
<210> 407
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.5
<400> 407
Glu Asp Leu His Ser Asn Gly His Thr Tyr Phe Leu
1 5 10
<210> 408
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.6
<400> 408
Glu Asp Leu His Ser Asn Gly Lys Thr Tyr Phe Leu
1 5 10
<210> 409
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.7
<400> 409
Glu Asp Leu His Ser Asn Gly Leu Thr Tyr Phe Leu
1 5 10
<210> 410
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.8
<400> 410
Glu Asp Leu His Ser Asn Ala Asp Thr Tyr Phe Leu
1 5 10
<210> 411
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.9
<400> 411
Glu Asp Leu His Ser Asn Ala Gln Thr Tyr Phe Leu
1 5 10
<210> 412
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.10
<400> 412
Glu Asp Leu His Ser Asn Ala Glu Thr Tyr Phe Leu
1 5 10
<210> 413
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.11
<400> 413
Glu Asp Leu His Ser Asn Ala Ala Thr Tyr Phe Leu
1 5 10
<210> 414
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.12
<400> 414
Glu Asp Leu His Ser Asn Ala His Thr Tyr Phe Leu
1 5 10
<210> 415
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.13
<400> 415
Glu Asp Leu His Ser Asn Ala Lys Thr Tyr Phe Leu
1 5 10
<210> 416
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3.v29.14
<400> 416
Glu Asp Leu His Ser Asn Ala Leu Thr Tyr Phe Leu
1 5 10
<210> 417
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.1
<400> 417
Asp Asp Leu His Ser Gly Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 418
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.2
<400> 418
Asp Asp Leu His Ser Thr Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 419
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.3
<400> 419
Asp Asp Leu His Ser Val Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 420
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.4
<400> 420
Asp Asp Leu His Ser Leu Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 421
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.5
<400> 421
Asp Asp Leu His Ser Ile Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 422
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.6
<400> 422
Asp Asp Leu His Ser Pro Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 423
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.7
<400> 423
Asp Asp Leu His Ser Phe Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 424
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.8
<400> 424
Asp Asp Leu His Ser Tyr Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 425
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.9
<400> 425
Asp Asp Leu His Ser His Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 426
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.10
<400> 426
Asp Asp Leu His Ser Lys Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 427
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v30.11
<400> 427
Asp Asp Leu His Ser Arg Gly Asn Thr Tyr Phe Leu
1 5 10
<210> 428
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.1
<400> 428
Asp Asp Leu His Ser Asn Ala Gly Thr Tyr Phe Leu
1 5 10
<210> 429
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.2
<400> 429
Asp Asp Leu His Ser Asn Ala Val Thr Tyr Phe Leu
1 5 10
<210> 430
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.3
<400> 430
Asp Asp Leu His Ser Asn Ala Ile Thr Tyr Phe Leu
1 5 10
<210> 431
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.4
<400> 431
Asp Asp Leu His Ser Asn Ala Pro Thr Tyr Phe Leu
1 5 10
<210> 432
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.5
<400> 432
Asp Asp Leu His Ser Asn Ala Phe Thr Tyr Phe Leu
1 5 10
<210> 433
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.6
<400> 433
Asp Asp Leu His Ser Asn Ala Tyr Thr Tyr Phe Leu
1 5 10
<210> 434
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.7
<400> 434
Asp Asp Leu His Ser Asn Ala Arg Thr Tyr Phe Leu
1 5 10
<210> 435
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.8
<400> 435
Asp Asp Leu His Ser Asn Ala Asn Val Tyr Phe Leu
1 5 10
<210> 436
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.9
<400> 436
Asp Asp Leu His Ser Asn Ala Asn Ile Tyr Phe Leu
1 5 10
<210> 437
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.10
<400> 437
Asp Asp Leu His Ser Asn Ala Asn Pro Tyr Phe Leu
1 5 10
<210> 438
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.11
<400> 438
Asp Asp Leu His Ser Asn Ala Asn Phe Tyr Phe Leu
1 5 10
<210> 439
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.12
<400> 439
Asp Asp Leu His Ser Asn Ala Asn Tyr Tyr Phe Leu
1 5 10
<210> 440
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.13
<400> 440
Asp Asp Leu His Ser Asn Ala Asn Asn Tyr Phe Leu
1 5 10
<210> 441
<211> 12
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu37D3-H9.v31.14
<400> 441
Asp Asp Leu His Ser Asn Ala Asn Arg Tyr Phe Leu
1 5 10
<210> 442
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11-H3.LC1
<400> 442
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Arg Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 443
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11-H3.LC2
<400> 443
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Arg Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 444
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11-H3.LC3
<400> 444
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Arg Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 445
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11-H3.LC4
<400> 445
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Arg Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 446
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11-H3.HC1
<400> 446
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 447
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11-H3.HC2
<400> 447
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 448
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11-H3.HC3
<400> 448
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 449
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11-H3.HC4
<400> 449
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 450
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11-H3.HC5
<400> 450
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 451
<211> 115
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu125B11-H3.HC6
<400> 451
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr
20 25 30
Phe Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 452
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.HC1
<400> 452
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 453
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.HC2
<400> 453
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 454
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.HC3
<400> 454
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Ala Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 455
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.HC4
<400> 455
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Arg Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 456
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.HC5
<400> 456
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 457
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.HC6
<400> 457
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 458
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.HC7
<400> 458
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 459
<211> 113
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.HC8
<400> 459
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 460
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.LC9
<400> 460
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 461
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.LC10
<400> 461
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 462
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.LC11
<400> 462
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 463
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.LC12
<400> 463
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 464
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.LC13
<400> 464
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 465
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.LC14
<400> 465
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 466
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.LC15
<400> 466
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 467
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu94B2.LC16
<400> 467
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 468
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.1 HVR-L1
<400> 468
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Thr Tyr Phe Glu
1 5 10 15
<210> 469
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.2 HVR-L1
<400> 469
Arg Ser Ser Gln Ser Ile Val His Ser Ser Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 470
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.3 HVR-L1
<400> 470
Arg Ser Ser Gln Ser Ile Val His Ser Asp Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 471
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.4 HVR-L1
<400> 471
Arg Ser Ser Gln Ser Ile Val His Ser Gln Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 472
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.5 HVR-L1
<400> 472
Arg Ser Ser Gln Ser Ile Val His Ser Glu Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 473
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.6 HVR-L1
<400> 473
Arg Ser Ser Gln Ser Ile Val His Ser Ala Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 474
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.7 HVR-L1
<400> 474
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asp Thr Tyr Phe Glu
1 5 10 15
<210> 475
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.8 HVR-L1
<400> 475
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Gln Thr Tyr Phe Glu
1 5 10 15
<210> 476
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.9 HVR-L1
<400> 476
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Glu Thr Tyr Phe Glu
1 5 10 15
<210> 477
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.10 HVR-L1
<400> 477
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Ala Thr Tyr Phe Glu
1 5 10 15
<210> 478
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v5.11 HVR-L1
<400> 478
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Ser Thr Tyr Phe Glu
1 5 10 15
<210> 479
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28 HVR-L1
<400> 479
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 480
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A2 HVR-L1
<400> 480
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 481
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A4 HVR-L1
<400> 481
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 482
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A6 HVR-L1
<400> 482
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 483
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A8 HVR-L1
<400> 483
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 484
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A10 HVR-L1
<400> 484
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 485
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A12 HVR-L1
<400> 485
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 486
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A14 HVR-L1
<400> 486
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 487
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A16 HVR-L1
<400> 487
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 488
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A18 HVR-L1
<400> 488
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 489
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A20 HVR-L1
<400> 489
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 490
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A22 HVR-L1
<400> 490
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 491
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A24 HVR-L1
<400> 491
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 492
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A26 HVR-L1
<400> 492
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 493
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A28 HVR-L1
<400> 493
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 494
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.A30 HVR-L1
<400> 494
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 495
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.B1 HVR-L1
<400> 495
Arg Ser Ser Gln Ser Ile Val His Ser Ile Gly Asn Thr Phe Phe Glu
1 5 10 15
<210> 496
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.B2 HVR-L1
<400> 496
Arg Ser Ser Gln Ser Ile Val His Ser Met Gly Asn Thr Phe Phe Glu
1 5 10 15
<210> 497
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.B3 HVR-L1
<400> 497
Arg Ser Ser Gln Ser Ile Val His Ser Gln Gly Asn Thr Trp Phe Glu
1 5 10 15
<210> 498
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.B4 HVR-L1
<400> 498
Arg Ser Ser Gln Ser Ile Val His Ser Gln Gly Asn Thr His Phe Glu
1 5 10 15
<210> 499
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.B6 HVR-L1
<400> 499
Arg Ser Ser Gln Ser Ile Val His Ser Asp Gly Asn Thr Arg Phe Glu
1 5 10 15
<210> 500
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.B7 HVR-L1
<400> 500
Arg Ser Ser Gln Ser Ile Val His Ser Asp Gly Asn Thr Lys Phe Glu
1 5 10 15
<210> 501
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.B8 HVR-L1
<400> 501
Arg Ser Ser Gln Ser Ile Val His Ser Glu Gly Asn Thr Arg Phe Glu
1 5 10 15
<210> 502
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.C1 HVR-L1
<400> 502
Arg Ser Ser Gln Ser Ile Val His Ser Asn Asn Asn Thr Tyr Phe Glu
1 5 10 15
<210> 503
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.C2 HVR-L1
<400> 503
Arg Ser Ser Gln Ser Ile Val His Ser Asn Asp Asn Thr Tyr Phe Glu
1 5 10 15
<210> 504
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.D1 HVR-L1
<400> 504
Arg Ser Ser Gln Ser Ile Val His Ala Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 505
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.E1 HVR-L1
<400> 505
Arg Ser Ser Gln Ser Ile Val Asn Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 506
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.E2 HVR-L1
<400> 506
Arg Ser Ser Gln Ser Ile Val Gln Ser Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 507
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.E3 HVR-L1
<400> 507
Arg Ser Ser Gln Ser Ile Val Asp Ser Asp Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 508
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.F1 HVR-L1
<400> 508
Arg Ser Ser Gln Ser Ile Val His Ser Asn Thr Asn Thr Tyr Phe Glu
1 5 10 15
<210> 509
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.F2 HVR-L1
<400> 509
Arg Ser Ser Gln Ser Ile Val His Thr Asn Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 510
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.F3 HVR-L1
<400> 510
Arg Ser Ser Gln Ser Ile Val His Thr Asn Ala Asn Thr Tyr Phe Glu
1 5 10 15
<210> 511
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.51 HVR-L1
<400> 511
Arg Ser Ser Gln Ser Ile Val His Ser His Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 512
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.52 HVR-L1
<400> 512
Arg Ser Ser Gln Ser Ile Val His Ser Lys Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 513
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.53 HVR-L1
<400> 513
Arg Ser Ser Gln Ser Ile Val His Ser Arg Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 514
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.54 HVR-L1
<400> 514
Arg Ser Ser Gln Ser Ile Val His Ser Leu Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 515
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.55 HVR-L1
<400> 515
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gln Asn Thr Tyr Phe Glu
1 5 10 15
<210> 516
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.56 HVR-L1
<400> 516
Arg Ser Ser Gln Ser Ile Val His Ser Asn Tyr Asn Thr Tyr Phe Glu
1 5 10 15
<210> 517
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v28.57 HVR-L1
<400> 517
Arg Ser Ser Gln Ser Ile Val His Ser Asn Phe Asn Thr Tyr Phe Glu
1 5 10 15
<210> 518
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.1 HVR-L1
<400> 518
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asp Thr Tyr Phe Glu
1 5 10 15
<210> 519
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.2 HVR-L1
<400> 519
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Gln Thr Tyr Phe Glu
1 5 10 15
<210> 520
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.3 HVR-L1
<400> 520
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Glu Thr Tyr Phe Glu
1 5 10 15
<210> 521
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.4 HVR-L1
<400> 521
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Ala Thr Tyr Phe Glu
1 5 10 15
<210> 522
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.5 HVR-L1
<400> 522
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly His Thr Tyr Phe Glu
1 5 10 15
<210> 523
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.6 HVR-L1
<400> 523
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Lys Thr Tyr Phe Glu
1 5 10 15
<210> 524
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.7 HVR-L1
<400> 524
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Leu Thr Tyr Phe Glu
1 5 10 15
<210> 525
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.8 HVR-L1
<400> 525
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asp Thr Tyr Phe Glu
1 5 10 15
<210> 526
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.9 HVR-L1
<400> 526
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Gln Thr Tyr Phe Glu
1 5 10 15
<210> 527
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.10 HVR-L1
<400> 527
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Glu Thr Tyr Phe Glu
1 5 10 15
<210> 528
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.11 HVR-L1
<400> 528
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Ala Thr Tyr Phe Glu
1 5 10 15
<210> 529
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.12 HVR-L1
<400> 529
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala His Thr Tyr Phe Glu
1 5 10 15
<210> 530
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.13 HVR-L1
<400> 530
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Lys Thr Tyr Phe Glu
1 5 10 15
<210> 531
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v29.14 HVR-L1
<400> 531
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Leu Thr Tyr Phe Glu
1 5 10 15
<210> 532
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.1 HVR-L1
<400> 532
Arg Ser Ser Gln Ser Ile Val His Ser Gly Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 533
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.2 HVR-L1
<400> 533
Arg Ser Ser Gln Ser Ile Val His Ser Thr Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 534
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.3 HVR-L1
<400> 534
Arg Ser Ser Gln Ser Ile Val His Ser Val Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 535
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.4 HVR-L1
<400> 535
Arg Ser Ser Gln Ser Ile Val His Ser Leu Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 536
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.5 HVR-L1
<400> 536
Arg Ser Ser Gln Ser Ile Val His Ser Ile Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 537
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.6 HVR-L1
<400> 537
Arg Ser Ser Gln Ser Ile Val His Ser Pro Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 538
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.7 HVR-L1
<400> 538
Arg Ser Ser Gln Ser Ile Val His Ser Phe Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 539
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.8 HVR-L1
<400> 539
Arg Ser Ser Gln Ser Ile Val His Ser Tyr Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 540
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.9 HVR-L1
<400> 540
Arg Ser Ser Gln Ser Ile Val His Ser His Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 541
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.10 HVR-L1
<400> 541
Arg Ser Ser Gln Ser Ile Val His Ser Lys Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 542
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v30.11 HVR-L1
<400> 542
Arg Ser Ser Gln Ser Ile Val His Ser Arg Gly Asn Thr Tyr Phe Glu
1 5 10 15
<210> 543
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.1 HVR-L1
<400> 543
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Gly Thr Tyr Phe Glu
1 5 10 15
<210> 544
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.2 HVR-L1
<400> 544
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Val Thr Tyr Phe Glu
1 5 10 15
<210> 545
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.3 HVR-L1
<400> 545
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Ile Thr Tyr Phe Glu
1 5 10 15
<210> 546
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.4 HVR-L1
<400> 546
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Pro Thr Tyr Phe Glu
1 5 10 15
<210> 547
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.5 HVR-L1
<400> 547
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Phe Thr Tyr Phe Glu
1 5 10 15
<210> 548
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.6 HVR-L1
<400> 548
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Tyr Thr Tyr Phe Glu
1 5 10 15
<210> 549
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.7 HVR-L1
<400> 549
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Arg Thr Tyr Phe Glu
1 5 10 15
<210> 550
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.8 HVR-L1
<400> 550
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Val Tyr Phe Glu
1 5 10 15
<210> 551
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.9 HVR-L1
<400> 551
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Ile Tyr Phe Glu
1 5 10 15
<210> 552
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.10 HVR-L1
<400> 552
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Pro Tyr Phe Glu
1 5 10 15
<210> 553
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.11 HVR-L1
<400> 553
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Phe Tyr Phe Glu
1 5 10 15
<210> 554
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.12 HVR-L1
<400> 554
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Tyr Tyr Phe Glu
1 5 10 15
<210> 555
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.13 HVR-L1
<400> 555
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Asn Tyr Phe Glu
1 5 10 15
<210> 556
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v31.14 HVR-L1
<400> 556
Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Arg Tyr Phe Glu
1 5 10 15
<210> 557
<211> 18
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Human Tau 7-24 peptide
<400> 557
Glu Phe Glu Val Met Glu Asp His Ala Gly Thr Tyr Gly Leu Gly Asp
1 5 10 15
Arg Lys
<210> 558
<211> 14
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Human Tau 7-20 peptide
<400> 558
Glu Phe Glu Val Met Glu Asp His Ala Gly Thr Tyr Gly Leu
1 5 10
<210> 559
<400> 559
000
<210> 560
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v39 weight chain variable districts (VH)
<400> 560
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 561
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v39 light chain variable districts (VL)
<400> 561
Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 562
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v39 HVR-H1
<400> 562
Ser Tyr Gly Met Ser
1 5
<210> 563
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v39 HVR-H2
<400> 563
Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 564
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v39 HVR-H3
<400> 564
Ser Tyr Ser Gly Ala Met Asp Tyr
1 5
<210> 565
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v39 HVR-L1
<400> 565
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 566
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v39 HVR-L2
<400> 566
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 567
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v39 HVR-L3
<400> 567
Phe Gln Gly Ser Leu Val Pro Trp Thr
1 5
<210> 568
<211> 444
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v39 IgG4-S228P.YTE heavy chains
<400> 568
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 569
<211> 219
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v39 IgG4-S228P.YTE light chains
<400> 569
Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 570
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v40 weight chain variable districts (VH)
<400> 570
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 571
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v40 light chain variable districts (VL)
<400> 571
Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Thr Asn Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 572
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v40 HVR-H1
<400> 572
Ser Tyr Gly Met Ser
1 5
<210> 573
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v40 HVR-H2
<400> 573
Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 574
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v40 HVR-H3
<400> 574
Ser Tyr Ser Gly Ala Met Asp Tyr
1 5
<210> 575
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v40 HVR-L1
<400> 575
Arg Ser Ser Gln Ser Ile Val His Ser Asn Thr Asn Thr Tyr Phe Glu
1 5 10 15
<210> 576
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v40 HVR-L2
<400> 576
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 577
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v40 HVR-L3
<400> 577
Phe Gln Gly Ser Leu Val Pro Trp Thr
1 5
<210> 578
<211> 444
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v40 IgG4-S228P.YTE heavy chains
<400> 578
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 579
<211> 219
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v40 IgG4-S228P.YTE light chains
<400> 579
Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Thr Asn Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 580
<211> 117
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v41 weight chain variable districts (VH)
<400> 580
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 581
<211> 112
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v41 light chain variable districts (VL)
<400> 581
Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Gln Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 582
<211> 5
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v41 HVR-H1
<400> 582
Ser Tyr Gly Met Ser
1 5
<210> 583
<211> 17
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v41 HVR-H2
<400> 583
Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 584
<211> 8
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v41 HVR-H3
<400> 584
Ser Tyr Ser Gly Ala Met Asp Tyr
1 5
<210> 585
<211> 16
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v41 HVR-L1
<400> 585
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Gln Thr Tyr Phe Glu
1 5 10 15
<210> 586
<211> 7
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v41 HVR-L2
<400> 586
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 587
<211> 9
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v41 HVR-L3
<400> 587
Phe Gln Gly Ser Leu Val Pro Trp Thr
1 5
<210> 588
<211> 444
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v41 IgG4-S228P.YTE heavy chains
<400> 588
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 589
<211> 219
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3.v41 IgG4-S228P.YTE light chains
<400> 589
Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Gln Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 590
<211> 444
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 IgG4 heavy chains
<400> 590
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 591
<211> 219
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v1 IgG4 light chains
<400> 591
Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 592
<211> 15
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：MAPT(10-24)
<400> 592
Val Met Glu Asp His Ala Gly Thr Tyr Gly Leu Gly Asp Arg Lys
1 5 10 15
<210> 593
<211> 23
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：MAPT(2-24)
<400> 593
Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly Thr
1 5 10 15
Tyr Gly Leu Gly Asp Arg Lys
20
<210> 594
<211> 33
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：MAPT(2-34)
<400> 594
Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly Thr
1 5 10 15
Tyr Gly Leu Gly Asp Arg Lys Asp Gln Gly Gly Tyr Thr Met His Gln
20 25 30
Asp
<210> 595
<211> 35
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：MAPT(10-44)
<400> 595
Val Met Glu Asp His Ala Gly Thr Tyr Gly Leu Gly Asp Arg Lys Asp
1 5 10 15
Gln Gly Gly Tyr Thr Met His Gln Asp Gln Glu Gly Asp Thr Asp Ala
20 25 30
Gly Leu Lys
35
<210> 596
<211> 23
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：MAPT(2-24)Y18A
<400> 596
Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly Thr
1 5 10 15
Ala Gly Leu Gly Asp Arg Lys
20
<210> 597
<211> 23
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：MAPT(2-24)L20A
<400> 597
Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly Thr
1 5 10 15
Tyr Gly Ala Gly Asp Arg Lys
20
<210> 598
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu113F5-F7.LC1
<400> 598
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Arg Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Ser Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 599
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu113F5-F7.LC2
<400> 599
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Arg Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Ser Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 600
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu113F5-F7.LC3
<400> 600
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Arg Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 601
<211> 107
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：hu113F5-F7.LC4
<400> 601
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Arg Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Thr Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 602
<211> 443
<212> PRT
<213>Artificial sequence
<220>
<223>Synthesis：Hu37D3-H9.v28.A4 IgG4-S228P.YTE des-K heavy chains
<400> 602
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440

Claims (63)

  1. A kind of 1. separated antibody for being incorporated into people Tau, wherein the antibody binding is in monomer Tau, oligomerization Tau, non-phosphoric acid Change Tau and phosphorylation Tau.
  2. 2. antibody as claimed in claim 1, wherein the antibody binding is into the epitope in acquaintance Tau amino acid 2 to 24.
  3. 3. the separated antibody as described in claim 1 or claim 2, it is monoclonal antibody.
  4. 4. the separated antibody as any one of preceding claims, it is human antibody, humanized antibody or inosculating antibody Body.
  5. 5. the antibody as any one of preceding claims, it is the antibody fragment with reference to people Tau.
  6. 6. the antibody as any one of preceding claims, wherein the people Tau includes SEQ ID NO：2 sequence.
  7. 7. the antibody as any one of preceding claims, wherein the antibody includes：
    A) include and be selected from SEQ ID NO：342nd, the HVR-H1 of 12,22,282 and 292 amino acid sequence；Comprising selected from SEQ ID NO：343rd, the HVR-H2 of 13,23,283 and 293 amino acid sequence；With comprising selected from SEQ ID NO：344th, 14,24,284 and The HVR-H3 of 294 amino acid sequence；Or
    B) include and be selected from SEQ ID NO：The HVR-H1 of 72 and 302 amino acid sequence；Comprising selected from SEQ ID NO：73 and 303 Amino acid sequence HVR-H2；With comprising selected from SEQ ID NO：The HVR-H3 of 74 and 304 amino acid sequence；
    C) SEQ ID NO are included：The HVR-H1 of 42 amino acid sequence；Include SEQ ID NO：The HVR- of 43 amino acid sequence H2；With include SEQ ID NO：The HVR-H3 of 44 amino acid sequence；
    D) SEQ ID NO are included：The HVR-H1 of 62 amino acid sequence；Include SEQ ID NO：The HVR- of 63 amino acid sequence H2；With include SEQ ID NO：The HVR-H3 of 64 amino acid sequence；
    E) SEQ ID NO are included：The HVR-H1 of 212 amino acid sequence；Include SEQ ID NO：213 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 214 amino acid sequence；
    F) SEQ ID NO are included：The HVR-H1 of 32 amino acid sequence；Include SEQ ID NO：The HVR- of 33 amino acid sequence H2；With include SEQ ID NO：The HVR-H3 of 34 amino acid sequence；Or
    G) SEQ ID NO are included：The HVR-H1 of 52 amino acid sequence；Include SEQ ID NO：The HVR- of 53 amino acid sequence H2；With include SEQ ID NO：The HVR-H3 of 54 amino acid sequence.
  8. 8. the antibody as any one of preceding claims, wherein the antibody includes：
    A) include and be selected from SEQ ID NO：345th, the HVR-L1 of 15,25,285,295 and 468 to 556 amino acid sequence；Comprising Selected from SEQ ID NO：346th, the HVR-L2 of 16,26,286 and 296 amino acid sequence；With comprising selected from SEQ ID NO：347、 17th, the HVR-L3 of 27,287 and 297 amino acid sequence；
    B) include and be selected from SEQ ID NO：The HVR-L1 of 75 and 305 amino acid sequence；Comprising selected from SEQ ID NO：76 and 306 Amino acid sequence HVR-L2；With comprising selected from SEQ ID NO：The HVR-L3 of 77 and 307 amino acid sequence；
    C) SEQ ID NO are included：The HVR-L1 of 45 amino acid sequence；Include SEQ ID NO：The HVR- of 46 amino acid sequence L2；With include SEQ ID NO：The HVR-I3 of 47 amino acid sequence；
    D) SEQ ID NO are included：The HVR-L1 of 65 amino acid sequence；Include SEQ ID NO：The HVR- of 66 amino acid sequence L2；With include SEQ ID NO：The HVR-L3 of 67 amino acid sequence；
    E) SEQ ID NO are included：The HVR-L1 of 215 amino acid sequence；Include SEQ ID NO：216 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 217 amino acid sequence；
    F) SEQ ID NO are included：The HVR-L1 of 35 amino acid sequence；Include SEQ ID NO：The HVR- of 36 amino acid sequence L2；With include SEQ ID NO：The HVR-L3 of 37 amino acid sequence；Or
    G) SEQ ID NO are included：The HVR-L1 of 55 amino acid sequence；Include SEQ ID NO：The HVR- of 56 amino acid sequence L2；With include SEQ ID NO：The HVR-L3 of 57 amino acid sequence.
  9. 9. the antibody as any one of preceding claims, wherein the antibody includes：
    A) include and be selected from SEQ ID NO：342nd, the HVR-H1 of 12,22,282 and 292 amino acid sequence；Comprising selected from SEQ ID NO：343rd, the HVR-H2 of 13,23,283 and 293 amino acid sequence；Comprising selected from SEQ ID NO：344th, 14,24,284 and The HVR-H3 of 294 amino acid sequence；Comprising selected from SEQ ID NO：345th, 15,25,285,295 and 468 to 556 amino acid The HVR-L1 of sequence；Comprising selected from SEQ ID NO：346th, the HVR-L2 of 16,26,286 and 296 amino acid sequence；With comprising Selected from SEQ ID NO：347th, the HVR-L3 of 17,27,287 and 297 amino acid sequence；
    B) include and be selected from SEQ ID NO：The HVR-H1 of 72 and 302 amino acid sequence；Comprising selected from SEQ ID NO：73 and 303 Amino acid sequence HVR-H2；Comprising selected from SEQ ID NO：The HVR-H3 of 74 and 304 amino acid sequence；Comprising selected from SEQ ID NO：The HVR-L1 of 75 and 305 amino acid sequence；Comprising selected from SEQ ID NO：76 and 306 amino acid sequence HVR-L2；With comprising selected from SEQ ID NO：The HVR-L3 of 77 and 307 amino acid sequence；
    C) SEQ ID NO are included：The HVR-H1 of 42 amino acid sequence；Include SEQ ID NO：The HVR- of 43 amino acid sequence H2；Include SEQ ID NO：The HVR-H3 of 44 amino acid sequence；Include SEQ ID NO：The HVR-L1 of 45 amino acid sequence； Include SEQ ID NO：The HVR-L2 of 46 amino acid sequence；With include SEQ ID NO：The HVR-L3 of 47 amino acid sequence；
    D) SEQ ID NO are included：The HVR-H1 of 62 amino acid sequence；Include SEQ ID NO：The HVR- of 63 amino acid sequence H2；Include SEQ ID NO：The HVR-H3 of 64 amino acid sequence；Include SEQ ID NO：The HVR-L1 of 65 amino acid sequence； Include SEQ ID NO：The HVR-L2 of 66 amino acid sequence；With include SEQ ID NO：The HVR-L3 of 67 amino acid sequence；
    E) SEQ ID NO are included：The HVR-H1 of 212 amino acid sequence；Include SEQ ID NO：213 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 214 amino acid sequence；Include SEQ ID NO：215 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 216 amino acid sequence；With include SEQ ID NO：217 amino acid sequence HVR-L3；
    F) SEQ ID NO are included：The HVR-H1 of 32 amino acid sequence；Include SEQ ID NO：The HVR- of 33 amino acid sequence H2；Include SEQ ID NO：The HVR-H3 of 34 amino acid sequence；Include SEQ ID NO：The HVR-L1 of 35 amino acid sequence； Include SEQ ID NO：The HVR-L2 of 36 amino acid sequence；With include SEQ ID NO：The HVR-L3 of 37 amino acid sequence； Or
    G) SEQ ID NO are included：The HVR-H1 of 52 amino acid sequence；Include SEQ ID NO：The HVR- of 53 amino acid sequence H2；Include SEQ ID NO：The HVR-H3 of 54 amino acid sequence；Include SEQ ID NO：The HVR-L1 of 55 amino acid sequence； Include SEQ ID NO：The HVR-L2 of 56 amino acid sequence；With include SEQ ID NO：The HVR-L3 of 57 amino acid sequence.
  10. 10. the antibody as any one of preceding claims, wherein the antibody includes：
    A) include with selected from SEQ ID NO：340th, 10,20,280,290,560,570 and 580 sequence is same with least 95% The weight chain variable district (VH) of the sequence of one property；
    B) include with selected from SEQ ID NO：341st, 11,21,281,291,561,571 and 581 sequence is same with least 95% The light chain variable district (VL) of the sequence of one property；
    C) such as the VH in (a) and such as the VL in (b)；
    D) include with selected from SEQ ID NO：70th, 300 and 452 to 459 sequence has the weight of at least sequence of 95% homogeneity Chain variable region (VH)；
    E) include with selected from SEQ ID NO：71st, 301 and 460 to 467 sequence is with the light of at least sequence of 95% homogeneity Chain variable region (VL)；
    F) such as the VH in (d) and such as the VL in (e)；
    G) include and SEQ ID NO：40 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    H) include and SEQ ID NO：41 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    I) such as the VH in (g) and such as the VL in (h)；
    J) include and SEQ ID NO：60 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    K) include and SEQ ID NO：61 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    L) such as the VH in (j) and such as the VL in (k)；
    M) include and SEQ ID NO：210 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    N) include and SEQ ID NO：211 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    O) such as the VH in (m) and such as the VL in (n)；
    P) include and SEQ ID NO：30 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Q) include and SEQ ID NO：31 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    R) such as the VH in (p) and such as the VL in (q)；
    S) include and SEQ ID NO：50 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    T) include and SEQ ID NO：51 have the light chain variable district (VL) of at least sequence of 95% homogeneity；Or
    U) such as the VH in (s) and such as the VL in (t).
  11. 11. the antibody as any one of preceding claims, wherein the antibody includes：
    A) include and be selected from SEQ ID NO：340th, the weight chain variable district (VH) of 10,20,280,290,560,570 and 580 sequence；
    B) include and be selected from SEQ ID NO：341st, the light chain variable district (VL) of 11,21,281,291,561,571 and 581 sequence；
    C) such as the VH in (a) and such as the VL in (b)；
    D) include and be selected from SEQ ID NO：70th, the weight chain variable district (VH) of 300 and 452 to 459 sequence；
    E) include and be selected from SEQ ID NO：71st, the light chain variable district (VL) of 301 and 460 to 467 sequence；
    F) such as the VH in (d) and such as the VL in (e)；
    G) SEQ ID NO are included：The weight chain variable district (VH) of 40 sequence；
    H) SEQ ID NO are included：The light chain variable district (VL) of 41 sequence；
    I) such as the VH in (g) and such as the VL in (h)；
    J) SEQ ID NO are included：The weight chain variable district (VH) of 60 sequence；
    K) SEQ ID NO are included：The light chain variable district (VL) of 61 sequence；
    L) such as the VH in (j) and such as the VL in (k)；
    M) SEQ ID NO are included：The weight chain variable district (VH) of 210 sequence；
    N) SEQ ID NO are included：The light chain variable district (VL) of 211 sequence；
    O) such as the VH in (m) and such as the VL in (n)；
    P) SEQ ID NO are included：The weight chain variable district (VH) of 30 sequence；
    Q) SEQ ID NO are included：The light chain variable district (VL) of 31 sequence；
    R) such as the VH in (p) and such as the VL in (q)；
    S) SEQ ID NO are included：The weight chain variable district (VH) of 50 sequence；
    T) SEQ ID NO are included：The light chain variable district (VL) of 51 sequence；Or
    U) such as the VH in (s) and such as the VL in (t).
  12. 12. the separated antibody as any one of preceding claims, wherein the antibody includes comprising SEQ ID NO：The HVR-H1 of 342 amino acid sequence；Include SEQ ID NO：The HVR-H2 of 343 amino acid sequence；Include SEQ ID NO：The HVR-H3 of 344 amino acid sequence；Include SEQ ID NO：The HVR-L1 of 345 amino acid sequence；Include SEQ ID NO：The HVR-L2 of 346 amino acid sequence；With include SEQ ID NO：The HVR-L3 of 347 amino acid sequence.
  13. 13. the separated antibody as any one of preceding claims, wherein the antibody includes comprising SEQ ID NO：The weight chain variable district of 340 amino acid sequence and include SEQ ID NO：The light chain variable district of 341 amino acid sequence.
  14. 14. the separated antibody as any one of preceding claims, wherein the antibody includes：
    A) include and SEQ ID NO：348 or SEQ ID NO：602 sequence has at least 95%, at least 97% or at least 99% The heavy chain of the amino acid sequence of homogeneity and comprising with SEQ ID NO：349 sequence has at least 95%, at least 97% or extremely The light chain of the amino acid sequence of few 99% homogeneity；Or
    B) SEQ ID NO are included：348 or SEQ ID NO：The heavy chain of 602 amino acid sequence and include SEQ ID NO：349 The light chain of amino acid sequence.
  15. A kind of 15. separated antibody for being incorporated into people Tau, wherein the antibody includes comprising SEQ ID NO：348 or SEQ ID NO：The heavy chain of 602 amino acid sequence and include SEQ ID NO：The light chain of 349 amino acid sequence.
  16. A kind of 16. separated antibody for being incorporated into people Tau, wherein the antibody is included by SEQ ID NO：348 or SEQ ID NO：602 amino acid sequence composition heavy chain and by SEQ ID NO：The light chain of 349 amino acid sequence composition.
  17. 17. the separated antibody as any one of claim 1 and 3 to 6, wherein the antibody binding is into acquaintance Tau Amino acid/11 9 to 33,19 to 42,28 to 44,37 to 51,100 to 114,109 to 123,118 to 132,154 to 168,172 to 177th, the epitope in 217 to 231 or 397 to 411.
  18. 18. such as the separated antibody any one of claim 1,3 to 6 and 17, wherein the antibody includes：
    A) SEQ ID NO are included：The HVR-H1 of 112 amino acid sequence；Include SEQ ID NO：113 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 114 amino acid sequence；
    B) SEQ ID NO are included：The HVR-H1 of 132 amino acid sequence；Include SEQ ID NO：133 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 134 amino acid sequence；
    C) SEQ ID NO are included：The HVR-H1 of 142 amino acid sequence；Include SEQ ID NO：143 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 144 amino acid sequence；
    D) SEQ ID NO are included：The HVR-H1 of 152 amino acid sequence；Include SEQ ID NO：153 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 154 amino acid sequence；
    E) SEQ ID NO are included：The HVR-H1 of 162 amino acid sequence；Include SEQ ID NO：163 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 164 amino acid sequence；
    F) SEQ ID NO are included：The HVR-H1 of 252 amino acid sequence；Include SEQ ID NO：253 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 254 amino acid sequence；
    G) SEQ ID NO are included：The HVR-H1 of 272 amino acid sequence；Include SEQ ID NO：273 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 274 amino acid sequence；
    H) SEQ ID NO are included：The HVR-H1 of 102 amino acid sequence；Include SEQ ID NO：103 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 104 amino acid sequence；
    I) SEQ ID NO are included：The HVR-H1 of 172 amino acid sequence；Include SEQ ID NO：173 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 174 amino acid sequence；
    J) SEQ ID NO are included：The HVR-H1 of 192 amino acid sequence；Include SEQ ID NO：193 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 194 amino acid sequence；
    K) SEQ ID NO are included：The HVR-H1 of 242 amino acid sequence；Include SEQ ID NO：243 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 244 amino acid sequence；
    L) include and be selected from SEQ ID NO：82nd, the HVR-H1 of 312,322 and 332 amino acid sequence；Comprising selected from SEQ ID NO：83rd, the HVR-H2 of 313,323 and 333 amino acid sequence；With comprising selected from SEQ ID NO：84th, 314,324 and 334 The HVR-H3 of amino acid sequence；
    M) SEQ ID NO are included：The HVR-H1 of 92 amino acid sequence；Include SEQ ID NO：The HVR- of 93 amino acid sequence H2；With include SEQ ID NO：The HVR-H3 of 94 amino acid sequence；
    N) SEQ ID NO are included：The HVR-H1 of 122 amino acid sequence；Include SEQ ID NO：123 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 124 amino acid sequence；
    O) SEQ ID NO are included：The HVR-H1 of 182 amino acid sequence；Include SEQ ID NO：183 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 184 amino acid sequence；
    P) SEQ ID NO are included：The HVR-H1 of 202 amino acid sequence；Include SEQ ID NO：203 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 204 amino acid sequence；
    Q) SEQ ID NO are included：The HVR-H1 of 222 amino acid sequence；Include SEQ ID NO：223 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 224 amino acid sequence；
    R) SEQ ID NO are included：The HVR-H1 of 232 amino acid sequence；Include SEQ ID NO：233 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 234 amino acid sequence；Or
    S) SEQ ID NO are included：The HVR-H1 of 262 amino acid sequence；Include SEQ ID NO：263 amino acid sequence HVR-H2；With include SEQ ID NO：The HVR-H3 of 264 amino acid sequence.
  19. 19. such as the separated antibody any one of claim 1,3 to 6,17 and 18, wherein the antibody includes：
    A) SEQ ID NO are included：The HVR-L1 of 115 amino acid sequence；Include SEQ ID NO：116 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 117 amino acid sequence；
    B) SEQ ID NO are included：The HVR-L1 of 135 amino acid sequence；Include SEQ ID NO：136 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 137 amino acid sequence；
    C) SEQ ID NO are included：The HVR-L1 of 145 amino acid sequence；Include SEQ ID NO：146 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 147 amino acid sequence；
    D) SEQ ID NO are included：The HVR-L1 of 155 amino acid sequence；Include SEQ ID NO：156 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 157 amino acid sequence；
    E) SEQ ID NO are included：The HVR-L1 of 165 amino acid sequence；Include SEQ ID NO：166 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 167 amino acid sequence；
    F) SEQ ID NO are included：The HVR-L1 of 255 amino acid sequence；Include SEQ ID NO：256 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 257 amino acid sequence；
    G) SEQ ID NO are included：The HVR-L1 of 275 amino acid sequence；Include SEQ ID NO：276 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 277 amino acid sequence；
    H) SEQ ID NO are included：The HVR-L1 of 105 amino acid sequence；Include SEQ ID NO：106 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 107 amino acid sequence；
    I) SEQ ID NO are included：The HVR-L1 of 175 amino acid sequence；Include SEQ ID NO：176 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 177 amino acid sequence；
    J) SEQ ID NO are included：The HVR-L1 of 195 amino acid sequence；Include SEQ ID NO：196 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 197 amino acid sequence；
    K) SEQ ID NO are included：The HVR-L1 of 245 amino acid sequence；Include SEQ ID NO：246 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 247 amino acid sequence；
    L) include and be selected from SEQ ID NO：85th, the HVR-L1 of 315,325 and 335 amino acid sequence；Comprising selected from SEQ ID NO：86th, the HVR-L2 of 316,326 and 336 amino acid sequence；With comprising selected from SEQ ID NO：87th, 317,327 and 337 The HVR-L3 of amino acid sequence；
    M) SEQ ID NO are included：The HVR-L1 of 95 amino acid sequence；Include SEQ ID NO：The HVR- of 96 amino acid sequence L2；With include SEQ ID NO：The HVR-L3 of 97 amino acid sequence；
    N) SEQ ID NO are included：The HVR-L1 of 125 amino acid sequence；Include SEQ ID NO：126 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 127 amino acid sequence；
    O) SEQ ID NO are included：The HVR-L1 of 185 amino acid sequence；Include SEQ ID NO：186 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 187 amino acid sequence；
    P) SEQ ID NO are included：The HVR-L1 of 205 amino acid sequence；Include SEQ ID NO：206 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 207 amino acid sequence；
    Q) SEQ ID NO are included：The HVR-L1 of 225 amino acid sequence；Include SEQ ID NO：226 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 227 amino acid sequence；
    R) SEQ ID NO are included：The HVR-L1 of 235 amino acid sequence；Include SEQ ID NO：236 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 237 amino acid sequence；Or
    S) SEQ ID NO are included：The HVR-L1 of 265 amino acid sequence；Include SEQ ID NO：266 amino acid sequence HVR-L2；With include SEQ ID NO：The HVR-L3 of 267 amino acid sequence.
  20. 20. such as the separated antibody any one of claim 1,3 to 6 and 17 to 19, wherein the antibody includes：
    A) SEQ ID NO are included：The HVR-H1 of 112 amino acid sequence；Include SEQ ID NO：113 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 114 amino acid sequence；Include SEQ ID NO：115 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 116 amino acid sequence；With include SEQ ID NO：117 amino acid sequence HVR-L3；
    B) SEQ ID NO are included：The HVR-H1 of 132 amino acid sequence；Include SEQ ID NO：133 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 134 amino acid sequence；Include SEQ ID NO：135 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 136 amino acid sequence；With include SEQ ID NO：137 amino acid sequence HVR-L3；
    C) SEQ ID NO are included：The HVR-H1 of 142 amino acid sequence；Include SEQ ID NO：143 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 144 amino acid sequence；Include SEQ ID NO：145 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 146 amino acid sequence；With include SEQ ID NO：147 amino acid sequence HVR-L3；
    D) SEQ ID NO are included：The HVR-H1 of 152 amino acid sequence；Include SEQ ID NO：153 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 154 amino acid sequence；Include SEQ ID NO：155 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 156 amino acid sequence；With include SEQ ID NO：157 amino acid sequence HVR-L3；
    E) SEQ ID NO are included：The HVR-H1 of 162 amino acid sequence；Include SEQ ID NO：163 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 164 amino acid sequence；Include SEQ ID NO：165 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 166 amino acid sequence；With include SEQ ID NO：167 amino acid sequence HVR-L3；
    F) SEQ ID NO are included：The HVR-H1 of 252 amino acid sequence；Include SEQ ID NO：253 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 254 amino acid sequence；Include SEQ ID NO：255 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 256 amino acid sequence；With include SEQ ID NO：257 amino acid sequence HVR-L3；Or
    G) SEQ ID NO are included：The HVR-H1 of 272 amino acid sequence；Include SEQ ID NO：273 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 274 amino acid sequence；Include SEQ ID NO：275 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 276 amino acid sequence；With include SEQ ID NO：277 amino acid sequence HVR-L3；
    H) SEQ ID NO are included：The HVR-H1 of 102 amino acid sequence；Include SEQ ID NO：103 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 104 amino acid sequence；Include SEQ ID NO：105 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 106 amino acid sequence；With include SEQ ID NO：107 amino acid sequence HVR-L3；
    I) SEQ ID NO are included：The HVR-H1 of 172 amino acid sequence；Include SEQ ID NO：173 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 174 amino acid sequence；Include SEQ ID NO：175 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 176 amino acid sequence；With include SEQ ID NO：177 amino acid sequence HVR-L3；
    J) SEQ ID NO are included：The HVR-H1 of 192 amino acid sequence；Include SEQ ID NO：193 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 194 amino acid sequence；Include SEQ ID NO：195 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 196 amino acid sequence；With include SEQ ID NO：197 amino acid sequence HVR-L3；Or
    K) SEQ ID NO are included：The HVR-H1 of 242 amino acid sequence；Include SEQ ID NO：243 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 244 amino acid sequence；Include SEQ ID NO：245 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 246 amino acid sequence；With include SEQ ID NO：247 amino acid sequence HVR-L3；
    L) include and be selected from SEQ ID NO：82nd, the HVR-H1 of 312,322 and 332 amino acid sequence；Comprising selected from SEQ ID NO：83rd, the HVR-H2 of 313,323 and 333 amino acid sequence；Comprising selected from SEQ ID NO：84th, 314,324 and 334 ammonia The HVR-H3 of base acid sequence；Comprising selected from SEQ ID NO：85th, the HVR-L1 of 315,325 and 335 amino acid sequence；Include choosing From SEQ ID NO：86th, the HVR-L2 of 316,326 and 336 amino acid sequence；With comprising selected from SEQ ID NO：87、317、 The HVR-L3 of 327 and 337 amino acid sequence；
    M) SEQ ID NO are included：The HVR-H1 of 92 amino acid sequence；Include SEQ ID NO：The HVR- of 93 amino acid sequence H2；Include SEQ ID NO：The HVR-H3 of 94 amino acid sequence；Include SEQ ID NO：The HVR-L1 of 95 amino acid sequence； Include SEQ ID NO：The HVR-L2 of 96 amino acid sequence；With include SEQ ID NO：The HVR-L3 of 97 amino acid sequence；
    N) SEQ ID NO are included：The HVR-H1 of 122 amino acid sequence；Include SEQ ID NO：123 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 124 amino acid sequence；Include SEQ ID NO：125 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 126 amino acid sequence；With include SEQ ID NO：127 amino acid sequence HVR-L3；
    O) SEQ ID NO are included：The HVR-H1 of 182 amino acid sequence；Include SEQ ID NO：183 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 184 amino acid sequence；Include SEQ ID NO：185 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 186 amino acid sequence；With include SEQ ID NO：187 amino acid sequence HVR-L3；
    P) SEQ ID NO are included：The HVR-H1 of 202 amino acid sequence；Include SEQ ID NO：203 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 204 amino acid sequence；Include SEQ ID NO：205 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 206 amino acid sequence；With include SEQ ID NO：207 amino acid sequence HVR-L3；
    Q) SEQ ID NO are included：The HVR-H1 of 222 amino acid sequence；Include SEQ ID NO：223 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 224 amino acid sequence；Include SEQ ID NO：225 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 226 amino acid sequence；With include SEQ ID NO：227 amino acid sequence HVR-L3；
    R) SEQ ID NO are included：The HVR-H1 of 232 amino acid sequence；Include SEQ ID NO：233 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 234 amino acid sequence；Include SEQ ID NO：235 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 236 amino acid sequence；With include SEQ ID NO：237 amino acid sequence HVR-L3；Or
    S) SEQ ID NO are included：The HVR-H1 of 262 amino acid sequence；Include SEQ ID NO：263 amino acid sequence HVR-H2；Include SEQ ID NO：The HVR-H3 of 264 amino acid sequence；Include SEQ ID NO：265 amino acid sequence HVR-L1；Include SEQ ID NO：The HVR-L2 of 266 amino acid sequence；With include SEQ ID NO：267 amino acid sequence HVR-L3.
  21. 21. such as the separated antibody any one of claim 1,3 to 6 and 17 to 20, wherein the antibody includes：
    A) include and SEQ ID NO：110 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    B) include and SEQ ID NO：111 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    C) such as the VH in (a) and such as the VL in (b)；
    D) include and SEQ ID NO：130 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    E) include and SEQ ID NO：131 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    F) such as the VH in (d) and such as the VL in (e)；
    G) include and SEQ ID NO：140 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    H) include and SEQ ID NO：141 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    I) such as the VH in (g) and such as the VL in (h)；
    J) include and SEQ ID NO：150 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    K) include and SEQ ID NO：151 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    L) such as the VH in (j) and such as the VL in (k)；
    M) include and SEQ ID NO：160 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    N) include and SEQ ID NO：161 have the light chain variable district (VL) of at least sequence of 95% homogeneity；Or
    O) such as the VH in (m) and such as the VL in (n)；
    P) include and SEQ ID NO：250 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Q) include and SEQ ID NO：251 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    R) such as the VH in (p) and such as the VL in (q)；
    S) include and SEQ ID NO：270 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    T) include and SEQ ID NO：271 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    U) such as the VH in (s) and such as the VL in (t)；
    V) include and SEQ ID NO：100 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    W) include and SEQ ID NO：101 have the light chain variable district (VL) of at least sequence of 95% homogeneity；Or
    X) such as the VH in (v) and such as the VL in (w)；
    Y) include and SEQ ID NO：170 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Z) include and SEQ ID NO：171 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    Aa) such as the VH in (y) and such as the VL in (z)；
    Bb) include and SEQ ID NO：190 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Cc) include and SEQ ID NO：191 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    Dd) such as the VH in (bb) and such as the VL in (cc)；
    Ee) include and SEQ ID NO：240 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Ff) include and SEQ ID NO：241 have the light chain variable district (VL) of at least sequence of 95% homogeneity；Or
    Gg) such as the VH in (ee) and such as the VL in (ff)；
    Hh) include with selected from SEQ ID NO：80th, 310,320,330 and 446 to 451 sequence has at least 95% homogeneity The weight chain variable district (VH) of sequence；
    Ii) include with selected from SEQ ID NO：81st, 311,321,331 and 442 to 445 sequence has at least 95% homogeneity The light chain variable district (VL) of sequence；
    Jj) such as the VH in (hh) and such as the VL in (ii)；
    Kk) include and SEQ ID NO：90 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Ll) include and SEQ ID NO：91 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    Mm) such as the VH in (kk) and such as the VL in (ll)；
    Nn) include and SEQ ID NO：120 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Oo) include and SEQ ID NO：121 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    Pp) such as the VH in (nn) and such as the VL in (oo)；
    Qq) include and SEQ ID NO：180 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Rr) include and SEQ ID NO：181 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    Ss) such as the VH in (qq) and such as the VL in (rr)；
    Tt) include and SEQ ID NO：200 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Uu) include and SEQ ID NO：201 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    Vv) such as the VH in (tt) and such as the VL in (uu)；
    Ww) include and SEQ ID NO：220 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Xx) include and SEQ ID NO：221 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    Yy) such as the VH in (ww) and such as the VL in (xx)；
    Zz) include and SEQ ID NO：230 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Aaa) include and SEQ ID NO：231 have the light chain variable district (VL) of at least sequence of 95% homogeneity；
    Bbb) such as the VH in (zz) and such as the VL in (aaa)；
    Ccc) include and SEQ ID NO：260 have the weight chain variable district (VH) of at least sequence of 95% homogeneity；
    Ddd) include and SEQ ID NO：261 have the light chain variable district (VL) of at least sequence of 95% homogeneity；Or
    Eee) such as the VH in (ccc) and such as the VL in (ddd).
  22. 22. such as the separated antibody any one of claim 1,3 to 6 and 17 to 21, wherein the antibody includes：
    A) SEQ ID NO are included：The weight chain variable district (VH) of 110 sequence；
    B) SEQ ID NO are included：The light chain variable district (VL) of 111 sequence；
    C) such as the VH in (a) and such as the VL in (b)；
    D) SEQ ID NO are included：The weight chain variable district (VH) of 130 sequence；
    E) SEQ ID NO are included：The light chain variable district (VL) of 131 sequence；
    F) such as the VH in (d) and such as the VL in (e)；
    G) SEQ ID NO are included：The weight chain variable district (VH) of 140 sequence；
    H) SEQ ID NO are included：The light chain variable district (VL) of 141 sequence；
    I) such as the VH in (g) and such as the VL in (h)；
    J) SEQ ID NO are included：The weight chain variable district (VH) of 150 sequence；
    K) SEQ ID NO are included：The light chain variable district (VL) of 151 sequence；
    L) such as the VH in (j) and such as the VL in (k)；
    M) SEQ ID NO are included：The weight chain variable district (VH) of 160 sequence；
    N) SEQ ID NO are included：The light chain variable district (VL) of 161 sequence；Or
    O) such as the VH in (m) and such as the VL in (n)；
    P) SEQ ID NO are included：The weight chain variable district (VH) of 250 sequence；
    Q) SEQ ID NO are included：The light chain variable district (VL) of 251 sequence；
    R) such as the VH in (p) and such as the VL in (q)；
    S) SEQ ID NO are included：The weight chain variable district (VH) of 270 sequence；
    T) SEQ ID NO are included：The light chain variable district (VL) of 271 sequence；Or
    U) such as the VH in (s) and such as the VL in (t)
    V) SEQ ID NO are included：The weight chain variable district (VH) of 100 sequence；
    W) SEQ ID NO are included：The light chain variable district (VL) of 101 sequence；Or
    X) such as the VH in (v) and such as the VL in (w)；
    Y) SEQ ID NO are included：The weight chain variable district (VH) of 170 sequence；
    Z) SEQ ID NO are included：The light chain variable district (VL) of 171 sequence；
    Aa) such as the VH in (y) and such as the VL in (z)；
    Bb SEQ ID NO) are included：The weight chain variable district (VH) of 190 sequence；
    Cc SEQ ID NO) are included：The light chain variable district (VL) of 191 sequence；
    Dd) such as the VH in (bb) and such as the VL in (cc)；
    Ee SEQ ID NO) are included：The weight chain variable district (VH) of 240 sequence；
    Ff SEQ ID NO) are included：The light chain variable district (VL) of 241 sequence；
    Gg) such as the VH in (ee) and such as the VL in (ff)；
    Hh) include and be selected from SEQ ID NO：80th, the weight chain variable district (VH) of 310,320,330 and 446 to 451 sequence；
    Ii) include and be selected from SEQ ID NO：81st, the light chain variable district (VL) of 311,321,331 and 442 to 445 sequence；
    Jj) such as the VH in (hh) and such as the VL in (ii)；
    Kk SEQ ID NO) are included：The weight chain variable district (VH) of 90 sequence；
    Ll SEQ ID NO) are included：The light chain variable district (VL) of 91 sequence；
    Mm) such as the VH in (kk) and such as the VL in (ll)；
    Nn SEQ ID NO) are included：The weight chain variable district (VH) of 120 sequence；
    Oo SEQ ID NO) are included：The light chain variable district (VL) of 121 sequence；
    Pp) such as the VH in (nn) and such as the VL in (oo)；
    Qq SEQ ID NO) are included：The weight chain variable district (VH) of 180 sequence；
    Rr SEQ ID NO) are included：The light chain variable district (VL) of 181 sequence；
    Ss) such as the VH in (qq) and such as the VL in (rr)；
    Tt SEQ ID NO) are included：The weight chain variable district (VH) of 200 sequence；
    Uu SEQ ID NO) are included：The light chain variable district (VL) of 201 sequence；
    Vv) such as the VH in (tt) and such as the VL in (uu)；
    Ww SEQ ID NO) are included：The weight chain variable district (VH) of 220 sequence；
    Xx SEQ ID NO) are included：The light chain variable district (VL) of 221 sequence；
    Yy) such as the VH in (ww) and such as the VL in (xx)；
    Zz SEQ ID NO) are included：The weight chain variable district (VH) of 230 sequence；
    Aaaa SEQ ID NO) are included：The light chain variable district (VL) of 231 sequence；
    Bbb) such as the VH in (zz) and such as the VL in (aaa)；
    Ccc SEQ ID NO) are included：The weight chain variable district (VH) of 260 sequence；
    Ddd SEQ ID NO) are included：The light chain variable district (VL) of 261 sequence；Or
    Eee) such as the VH in (ccc) and such as the VL in (ddd).
  23. 23. the separated antibody as any one of preceding claims, wherein the antibody is IgG1 or IgG4 antibody.
  24. 24. separated antibody as claimed in claim 23, wherein the antibody is IgG4 antibody.
  25. 25. separated antibody as claimed in claim 24, wherein the antibody is mutated comprising M252Y, S254T and T256E.
  26. 26. the separated antibody as described in claim 24 or claim 25, wherein the antibody is mutated comprising S228P.
  27. 27. the separated antibody as any one of claim 1 to 13 and 17 to 26, it is antibody fragment.
  28. 28. the separated antibody as any one of preceding claims, wherein the antibody with less than 100nM, be less than The 75nM or K less than 50nMDWith reference to each of monomer Tau, phosphorylation Tau, non-phosphorylating Tau and oligomerization Tau.
  29. 29. the separated antibody as any one of preceding claims, it combines machin Tau (SEQ ID NO：4).
  30. 30. a kind of separated nucleic acid, it encodes the antibody as any one of preceding claims.
  31. 31. a kind of host cell, it includes nucleic acid as claimed in claim 30.
  32. 32. a kind of method for producing antibody, it, which is included in, is suitable for producing culture such as claim 31 under conditions of the antibody Described host cell.
  33. 33. a kind of immunoconjugates, its separated antibody and second for including as any one of claim 1 to 29 is controlled Treat agent.
  34. 34. a kind of labeled antibody, it includes the antibody and detectable mark as any one of claim 1 to 28 Note.
  35. 35. a kind of pharmaceutical composition, it is comprising the separated antibody as any one of claim 1 to 29 and pharmaceutically Acceptable carrier.
  36. 36. a kind of method for treating Tau protein related diseases, it includes applying such as to the individual with Tau protein related diseases Antibody or pharmaceutical composition as claimed in claim 33 any one of claim 1 to 29.
  37. 37. method as claimed in claim 36, wherein the Tau protein related diseases are Protein tau disease.
  38. 38. method as claimed in claim 37, wherein Protein tau disease is neurodegenerative Protein tau disease.
  39. 39. the method as described in claim 37 or claim 38, wherein Protein tau disease selected from Alzheimer disease, Amyotrophic lateral sclerosis, Parkinson's, gram refined Er Shi diseases, dementia pugilistica, Down syndrome, lattice are applied and thank to San Shi diseases, forgive Body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam Parkinson are comprehensive Simulator sickness-dementia complex, with non-Guam type motor neuron disease of neurofibrillary tangles, argyrophilic grain dementia, cortex base Bottom core degeneration disease, with the Diffuse neurofibrillary entanglement of calcification, Frontotemporal dementia, chain companion's pa gold in No. 17 chromosome It is the Frontotemporal dementia of gloomy syndrome, Hallervorden Spatz disease, multiple system atrophy, c-type Niemann-Pick disease, pale It is glial cells hyperplasia disease under ball-ponto-nigral degeneration disease, Pick disease, progressive cortex, paralysis on progressive core, subacute hard The property changed panencephalitis, only entanglement type dementia, postencephalitic parkinsonism and myotonia atrophica.
  40. 40. the method as any one of claim 37 to 39, wherein Protein tau disease is Alzheimer disease or enters Benumbed on row core.
  41. 41. a kind of keep in individual or improve cognition and memory ability or slow down the method for the loss of memory, it is included using as weighed Profit requires the antibody or pharmaceutical composition as claimed in claim 35 any one of 1 to 29.
  42. 42. a kind of reduce Tau albumen in individual, non-phosphorylating Tau albumen, phosphorylated Tau protein or peroxophosphoric acid Tau albumen Horizontal method, it is included using the antibody as any one of claim 1 to 29 or medicine as claimed in claim 35 Compositions.
  43. 43. the method as any one of claim 36 to 42, wherein methods described include applying at least one extra treatment Method.
  44. 44. method as claimed in claim 43, wherein the additional therapy be selected from neurologic agent, corticosteroid, antibiotic, Antivirotic, anti-Tau antibody, Tau inhibitor, anti-amyloid beta antibody, beta-amyloid aggregation inhibitor, anti-BACE1 Antibody and BACE1 inhibitor.
  45. 45. the separated antibody as any one of claim 1 to 29, it is used as medicament.
  46. 46. the separated antibody as any one of claim 1 to 29, it is used to treat Protein tau disease in individual.
  47. 47. separated antibody as claimed in claim 46, wherein Protein tau disease is neurodegenerative Protein tau disease.
  48. 48. the separated antibody as described in claim 46 or claim 47, wherein Protein tau disease is selected from A Erci The silent disease in sea, amyotrophic lateral sclerosis, Parkinson's, gram refined Er Shi diseases, dementia pugilistica, Down syndrome, lattice are applied and thank to San Shi Disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam pa Gloomy syndrome-the dementia complex of gold, with non-Guam type motor neuron disease of neurofibrillary tangles, argyrophilic grain dementia, Corticobasal degeneration, with the Diffuse neurofibrillary entanglement of calcification, Frontotemporal dementia, chain in No. 17 chromosome With the Frontotemporal dementia of parkinson's syndrome, Hallervorden Spatz disease, multiple system atrophy, c-type Niemann-Pick disease, It is glial cells hyperplasia disease under globus pallidus-ponto-nigral degeneration disease, Pick disease, progressive cortex, paralysis on progressive core, sub- anxious Property sclerosing panencephalitis, only entanglement type is dull-witted, postencephalitic parkinsonism and myotonia atrophica.
  49. 49. the separated antibody as any one of claim 46 to 48, wherein Protein tau disease is alzheimer ' Benumbed on silent disease or progressive core.
  50. 50. the separated antibody as any one of claim 1 to 29, it is used to cognition is kept or improved in individual Memory capability slows down the loss of memory.
  51. 51. the separated antibody as any one of claim 1 to 29, it is used to reduce Tau albumen, phosphoric acid in individual Change the level of Tau albumen, non-phosphorylating Tau albumen or peroxophosphoric acid Tau albumen.
  52. 52. the separated antibody as any one of claim 46 to 51, wherein the antibody and at least one are extra Therapy is used together.
  53. 53. separated antibody as claimed in claim 52, wherein the additional therapy is selected from neurologic agent, cortex class is consolidated Alcohol, antibiotic, antivirotic, anti-Tau antibody, anti-amyloid beta antibody, anti-BACE1 antibody and BACE1 inhibitor.
  54. 54. a kind of purposes of antibody as any one of claim 1 to 29, it, which is used to manufacture, is used to treat in individual The medicament of Tau protein related diseases.
  55. 55. purposes as claimed in claim 50, wherein the Tau protein related diseases are Protein tau disease.
  56. 56. purposes as claimed in claim 51, wherein Protein tau disease is neurodegenerative Protein tau disease.
  57. 57. the purposes as described in claim 51 or claim 52, wherein Protein tau disease selected from Alzheimer disease, Amyotrophic lateral sclerosis, Parkinson's, gram refined Er Shi diseases, dementia pugilistica, Down syndrome, lattice are applied and thank to San Shi diseases, forgive Body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam Parkinson are comprehensive Simulator sickness-dementia complex, with non-Guam type motor neuron disease of neurofibrillary tangles, argyrophilic grain dementia, cortex base Bottom core degeneration disease, with the Diffuse neurofibrillary entanglement of calcification, Frontotemporal dementia, chain companion's pa gold in No. 17 chromosome It is the Frontotemporal dementia of gloomy syndrome, Hallervorden Spatz disease, multiple system atrophy, c-type Niemann-Pick disease, pale It is glial cells hyperplasia disease under ball-ponto-nigral degeneration disease, Pick disease, progressive cortex, paralysis on progressive core, subacute hard The property changed panencephalitis, only entanglement type dementia, postencephalitic parkinsonism and myotonia atrophica.
  58. 58. the purposes as any one of claim 51 to 53, wherein Protein tau disease is Alzheimer disease or enters Benumbed on row core.
  59. 59. a kind of purposes of antibody as any one of claim 1 to 29, it, which is used to manufacture, is used to keep in individual Or improve cognition and memory ability or slow down the medicament of the loss of memory.
  60. 60. the purposes as any one of claim 54 to 59, wherein the medicament is used for and at least one additional therapy Apply together.
  61. 61. purposes as claimed in claim 60, wherein the additional therapy be selected from neurologic agent, corticosteroid, antibiotic, Antivirotic, anti-Tau antibody, anti-amyloid beta antibody, anti-BACE1 antibody and BACE1 inhibitor.
  62. 62. one kind detection neurofibrillary tangles, neuropil thread or the neuritic method of dystrophic, it includes making sample Product contact with the antibody as any one of claim 1 to 29.
  63. 63. method as claimed in claim 56, wherein the sample is brain sample, celiolymph sample or blood sample.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113005096A (en) * 2021-01-19 2021-06-22 华中科技大学 Hybridoma cell strain secreting anti-serine phosphorylation tau protein monoclonal antibody
CN114174515A (en) * 2019-05-27 2022-03-11 英属哥伦比亚大学 Conformation-specific epitopes in tau, antibodies thereto and methods related thereto

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA035943B1 (en) 2013-03-13 2020-09-03 Протена Биосайенсес Лимитед Antibody binding to human tau protein
MA41867A (en) 2015-04-01 2018-02-06 Anaptysbio Inc T-CELL IMMUNOGLOBULIN AND MUCINE PROTEIN 3 ANTIBODIES (TIM-3)
US10112990B2 (en) 2015-06-05 2018-10-30 Genentech, Inc. Anti-Tau antibodies and methods of use
MA42380A (en) 2015-07-06 2018-05-16 Ucb Biopharma Sprl ANTIBODIES BONDING TO TAU
CA3022515A1 (en) 2016-05-02 2017-11-09 Prothena Biosciences Limited Antibodies recognizing tau
US10752679B2 (en) 2016-05-02 2020-08-25 Prothena Biosciences Limited Tau immunotherapy
WO2018085469A2 (en) 2016-11-01 2018-05-11 Anaptysbio, Inc. Antibodies directed against t cell immunoglobulin and mucin protein 3 (tim-3)
CN117820467A (en) * 2016-12-07 2024-04-05 基因泰克公司 anti-TAU antibodies and methods of use
KR20230146126A (en) * 2016-12-07 2023-10-18 제넨테크, 인크. Anti-tau antibodies and methods of use
KR20190134997A (en) * 2017-02-17 2019-12-05 데날리 테라퓨틱스 인크. Anti-TAU Antibodies and Methods of Use thereof
SG10201911225WA (en) * 2017-03-28 2020-01-30 Genentech Inc Methods of treating neurodegenerative diseases
CN110881274A (en) 2017-05-02 2020-03-13 普罗塞纳生物科学有限公司 Antibodies recognizing TAU
WO2019018828A1 (en) * 2017-07-20 2019-01-24 Cytomx Therapeutics, Inc. Methods of qualitatively and/or quantitatively analyzing properties of activatable antibodies and uses thereof
MA50397A (en) 2017-10-16 2020-08-26 Eisai R&D Man Co Ltd ANTI-BODY ANTI-TAU AND THEIR USES
EP3700556A2 (en) 2017-10-25 2020-09-02 Janssen Pharmaceuticals, Inc. Compositions of phosphorylated tau peptides and uses thereof
NL2020520B1 (en) * 2018-03-02 2019-09-12 Labo Bio Medical Invest B V Multispecific binding molecules for the prevention, treatment and diagnosis of neurodegenerative disorders
SG11202008574VA (en) * 2018-03-05 2020-10-29 Janssen Pharmaceutica Nv Assays to detect neurodegeneration
WO2019171259A1 (en) 2018-03-05 2019-09-12 Janssen Pharmaceutica Nv Anti-phf-tau antibodies and uses thereof
EA202092122A1 (en) * 2018-03-08 2020-12-03 Фейнз Терапьютикс, Инк. ANTIBODIES AGAINST TIP-1 AND THEIR APPLICATION
WO2020097561A1 (en) * 2018-11-08 2020-05-14 Prothena Biosciences Limited Antibodies recognizing tau
CN113286823A (en) * 2019-01-28 2021-08-20 上海拓界生物医药科技有限公司 anti-CD 79B antibody, antigen binding fragment thereof and medical application thereof
CN113710269A (en) 2019-02-08 2021-11-26 Ac免疫有限公司 Safe administration method of phosphorylated Tau peptide vaccine
MX2021009440A (en) * 2019-02-08 2021-09-10 Prothena Biosciences Ltd Antibodies recognizing tau.
PE20212324A1 (en) 2019-03-03 2021-12-14 Prothena Biosciences Ltd ANTIBODIES THAT RECOGNIZE TAU
EP3965817A4 (en) 2019-04-24 2023-11-22 Janssen Pharmaceuticals, Inc. Heterologous administration of tau vaccines
JP7227895B2 (en) * 2019-12-23 2023-02-22 株式会社堀場製作所 Interaction detection method, interaction detection device, and biochip regeneration kit
AU2022332303A1 (en) * 2021-08-27 2024-02-01 Genentech, Inc. Methods of treating tau pathologies

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013007839A1 (en) * 2011-07-14 2013-01-17 Adx Neurosciences Nv Antibodies to phosphorylated tau aggregates
WO2014059442A2 (en) * 2012-10-12 2014-04-17 Arizona Board Agents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University Antibody based reagents that specifically recognize toxic oligomeric forms of tau
WO2014150877A2 (en) * 2013-03-15 2014-09-25 Ac Immune S.A. Anti-tau antibodies and methods of use
WO2014200921A1 (en) * 2013-06-10 2014-12-18 Ipierian, Inc. Methods of treating a tauopathy

Family Cites Families (128)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4737456A (en) 1985-05-09 1988-04-12 Syntex (U.S.A.) Inc. Reducing interference in ligand-receptor binding assays
US4676980A (en) 1985-09-23 1987-06-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Target specific cross-linked heteroantibodies
US6548640B1 (en) 1986-03-27 2003-04-15 Btg International Limited Altered antibodies
US5811310A (en) 1986-09-30 1998-09-22 Albert Einstein College Of Medicine Of Yeshiva Univ. The Alz-50 monoclonal antibody and diagnostic assay for alzheimer's disease
IL85035A0 (en) 1987-01-08 1988-06-30 Int Genetic Eng Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same
EP0307434B2 (en) 1987-03-18 1998-07-29 Scotgen Biopharmaceuticals, Inc. Altered antibodies
AU634186B2 (en) 1988-11-11 1993-02-18 Medical Research Council Single domain ligands, receptors comprising said ligands, methods for their production, and use of said ligands and receptors
DE3920358A1 (en) 1989-06-22 1991-01-17 Behringwerke Ag BISPECIFIC AND OLIGO-SPECIFIC, MONO- AND OLIGOVALENT ANTI-BODY CONSTRUCTS, THEIR PRODUCTION AND USE
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US5959177A (en) 1989-10-27 1999-09-28 The Scripps Research Institute Transgenic plants expressing assembled secretory antibodies
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
AU7121191A (en) * 1990-02-26 1991-10-10 Albert Einstein College Of Medicine Of Yeshiva University Diagnostic assay for alzheimer's disease
US5770429A (en) 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
EP0564531B1 (en) 1990-12-03 1998-03-25 Genentech, Inc. Enrichment method for variant proteins with altered binding properties
US5571894A (en) 1991-02-05 1996-11-05 Ciba-Geigy Corporation Recombinant antibodies specific for a growth factor receptor
LU91067I2 (en) 1991-06-14 2004-04-02 Genentech Inc Trastuzumab and its variants and immunochemical derivatives including immotoxins
GB9114948D0 (en) 1991-07-11 1991-08-28 Pfizer Ltd Process for preparing sertraline intermediates
US7018809B1 (en) 1991-09-19 2006-03-28 Genentech, Inc. Expression of functional antibody fragments
US5587458A (en) 1991-10-07 1996-12-24 Aronex Pharmaceuticals, Inc. Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof
WO1993008829A1 (en) 1991-11-04 1993-05-13 The Regents Of The University Of California Compositions that mediate killing of hiv-infected cells
ATE503496T1 (en) 1992-02-06 2011-04-15 Novartis Vaccines & Diagnostic BIOSYNTHETIC BINDING PROTEIN FOR TUMOR MARKERS
ES2091684T3 (en) 1992-11-13 1996-11-01 Idec Pharma Corp THERAPEUTIC APPLICATION OF CHEMICAL AND RADIO-MARKED ANTIBODIES AGAINST THE RESTRICTED DIFFERENTIATION ANTIGEN OF HUMAN B-LYMPHOCYTES FOR THE TREATMENT OF B-CELL LYMPHOMA.
AU691811B2 (en) 1993-06-16 1998-05-28 Celltech Therapeutics Limited Antibodies
US5789199A (en) 1994-11-03 1998-08-04 Genentech, Inc. Process for bacterial production of polypeptides
US5840523A (en) 1995-03-01 1998-11-24 Genetech, Inc. Methods and compositions for secretion of heterologous polypeptides
US5731168A (en) 1995-03-01 1998-03-24 Genentech, Inc. Method for making heteromultimeric polypeptides
US5869046A (en) 1995-04-14 1999-02-09 Genentech, Inc. Altered polypeptides with increased half-life
US6267958B1 (en) 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
GB9603256D0 (en) 1996-02-16 1996-04-17 Wellcome Found Antibodies
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
EP0994903B1 (en) 1997-06-24 2005-05-25 Genentech, Inc. Methods and compositions for galactosylated glycoproteins
US6040498A (en) 1998-08-11 2000-03-21 North Caroline State University Genetically engineered duckweed
WO1999022764A1 (en) 1997-10-31 1999-05-14 Genentech, Inc. Methods and compositions comprising glycoprotein glycoforms
US6610833B1 (en) 1997-11-24 2003-08-26 The Institute For Human Genetics And Biochemistry Monoclonal human natural antibodies
BR9813365A (en) 1997-12-05 2004-06-15 Scripps Research Inst Method for Production and Humanization of a Mouse Monoclonal Antibody
PT1068241E (en) 1998-04-02 2007-11-19 Genentech Inc Antibody variants and fragments thereof
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
DK1071700T3 (en) 1998-04-20 2010-06-07 Glycart Biotechnology Ag Glycosylation modification of antibodies to enhance antibody-dependent cellular cytotoxicity
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
EP2364997A3 (en) 1999-01-15 2012-07-04 Genentech, Inc. Polypeptide variants with altered effector function
ES2420835T3 (en) 1999-04-09 2013-08-27 Kyowa Hakko Kirin Co., Ltd. Procedure to control the activity of immunofunctional molecules
US7125978B1 (en) 1999-10-04 2006-10-24 Medicago Inc. Promoter for regulating expression of foreign genes
ES2248127T3 (en) 1999-10-04 2006-03-16 Medicago Inc. METHOD FOR REGULATING THE TRANSCRIPTION OF FOREIGN GENES IN THE PRESENCE OF NIGTROGEN.
EP1229125A4 (en) 1999-10-19 2005-06-01 Kyowa Hakko Kogyo Kk Process for producing polypeptide
IL149809A0 (en) 1999-12-15 2002-11-10 Genentech Inc Shotgun scanning, a combinatorial method for mapping functional protein epitopes
LT2857516T (en) 2000-04-11 2017-09-11 Genentech, Inc. Multivalent antibodies and uses therefor
BR0114475A (en) 2000-10-06 2003-12-23 Kyowa Hakko Kogyo Kk Cell for the production of antibody composition
US7064191B2 (en) 2000-10-06 2006-06-20 Kyowa Hakko Kogyo Co., Ltd. Process for purifying antibody
US6946292B2 (en) 2000-10-06 2005-09-20 Kyowa Hakko Kogyo Co., Ltd. Cells producing antibody compositions with increased antibody dependent cytotoxic activity
US6596541B2 (en) 2000-10-31 2003-07-22 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
IL155977A0 (en) 2000-11-30 2003-12-23 Medarex Inc Transgenic transchromosomal rodents for making human antibodies
ES2727425T3 (en) 2000-12-12 2019-10-16 Medimmune Llc Molecules with prolonged half-lives, compositions and uses thereof
AT500379B8 (en) 2001-02-02 2009-08-15 Axon Neuroscience TAU PROTEINS
NZ592087A (en) 2001-08-03 2012-11-30 Roche Glycart Ag Antibody glycosylation variants having increased antibody-dependent cellular cytotoxicity
JP2005532253A (en) 2001-10-25 2005-10-27 ジェネンテック・インコーポレーテッド Glycoprotein composition
US20040093621A1 (en) 2001-12-25 2004-05-13 Kyowa Hakko Kogyo Co., Ltd Antibody composition which specifically binds to CD20
AU2003236019A1 (en) 2002-04-09 2003-10-20 Kyowa Hakko Kirin Co., Ltd. Drug containing antibody composition appropriate for patient suffering from Fc Gamma RIIIa polymorphism
AU2003236015A1 (en) 2002-04-09 2003-10-20 Kyowa Hakko Kirin Co., Ltd. Process for producing antibody composition
EP1500698B1 (en) 2002-04-09 2011-03-30 Kyowa Hakko Kirin Co., Ltd. Cell with depression or deletion of the activity of protein participating in gdp-fucose transport
US20040259150A1 (en) 2002-04-09 2004-12-23 Kyowa Hakko Kogyo Co., Ltd. Method of enhancing of binding activity of antibody composition to Fcgamma receptor IIIa
EP1498485A4 (en) 2002-04-09 2006-09-06 Kyowa Hakko Kogyo Kk Cells with modified genome
JPWO2003084569A1 (en) 2002-04-09 2005-08-11 協和醗酵工業株式会社 Antibody composition-containing medicine
AU2003239966B9 (en) 2002-06-03 2010-08-26 Genentech, Inc. Synthetic antibody phage libraries
US7361740B2 (en) 2002-10-15 2008-04-22 Pdl Biopharma, Inc. Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis
JP4351674B2 (en) 2002-12-16 2009-10-28 ジェネンテック・インコーポレーテッド Immunoglobulin variants and their use and use
AU2003291910B2 (en) 2002-12-24 2009-10-01 Bellus Health (International) Limited Therapeutic formulations for the treatment of beta-amyloid related diseases
EP1585767A2 (en) 2003-01-16 2005-10-19 Genentech, Inc. Synthetic antibody phage libraries
US7871607B2 (en) 2003-03-05 2011-01-18 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases
US20060104968A1 (en) 2003-03-05 2006-05-18 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases
AU2004279742A1 (en) 2003-10-08 2005-04-21 Kyowa Hakko Kirin Co., Ltd. Fused protein composition
JPWO2005035778A1 (en) 2003-10-09 2006-12-21 協和醗酵工業株式会社 Method for producing antibody composition using RNA that suppresses function of α1,6-fucosyltransferase
WO2005044859A2 (en) 2003-11-05 2005-05-19 Glycart Biotechnology Ag Cd20 antibodies with increased fc receptor binding affinity and effector function
WO2005053742A1 (en) 2003-12-04 2005-06-16 Kyowa Hakko Kogyo Co., Ltd. Medicine containing antibody composition
AU2005230848B9 (en) 2004-03-31 2011-06-02 Genentech, Inc. Humanized anti-TGF-beta antibodies
US7785903B2 (en) 2004-04-09 2010-08-31 Genentech, Inc. Variable domain library and uses
EP2067789A1 (en) 2004-04-13 2009-06-10 F. Hoffmann-La Roche Ag Anti-P selectin antibodies
TWI309240B (en) 2004-09-17 2009-05-01 Hoffmann La Roche Anti-ox40l antibodies
RU2412947C2 (en) 2004-09-23 2011-02-27 Дженентек, Инк. Antibodies, constructed on cysteine basis and their conjugates
JO3000B1 (en) 2004-10-20 2016-09-05 Genentech Inc Antibody Formulations.
ES2577292T3 (en) 2005-11-07 2016-07-14 Genentech, Inc. Binding polypeptides with diversified VH / VL hypervariable sequences and consensus
EP1973951A2 (en) 2005-12-02 2008-10-01 Genentech, Inc. Binding polypeptides with restricted diversity sequences
WO2007134050A2 (en) 2006-05-09 2007-11-22 Genentech, Inc. Binding polypeptides with optimized scaffolds
EP2059533B1 (en) 2006-08-30 2012-11-14 Genentech, Inc. Multispecific antibodies
GB0624500D0 (en) 2006-12-07 2007-01-17 Istituto Superiore Di Sanito A novel passive vaccine for candida infections
US20080226635A1 (en) 2006-12-22 2008-09-18 Hans Koll Antibodies against insulin-like growth factor I receptor and uses thereof
CN100592373C (en) 2007-05-25 2010-02-24 群康科技(深圳)有限公司 Liquid crystal panel drive device and its drive method
CA2709847C (en) 2008-01-07 2018-07-10 Amgen Inc. Method for making antibody fc-heterodimeric molecules using electrostatic steering effects
UA107571C2 (en) 2009-04-03 2015-01-26 PHARMACEUTICAL COMPOSITION
US8609097B2 (en) 2009-06-10 2013-12-17 Hoffmann-La Roche Inc. Use of an anti-Tau pS422 antibody for the treatment of brain diseases
JP6146913B2 (en) * 2010-08-02 2017-06-14 リジェネロン・ファーマシューティカルズ・インコーポレイテッドＲｅｇｅｎｅｒｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． Mice producing a binding protein containing a VL domain
HUE027649T2 (en) 2010-10-07 2016-10-28 Ac Immune Sa Antibodies recognising phospho-tau
ES2686550T3 (en) 2010-10-11 2018-10-18 Biogen International Neuroscience Gmbh Human anti-tau antibodies
EA201390923A1 (en) 2010-12-22 2013-12-30 Сефалон Острэйлиа Пти Лтд. MODIFIED ANTIBODY WITH AN IMPROVED ELEMENTATION SEMIUM PERIOD
CA2826286C (en) 2011-01-31 2021-09-21 Intellect Neurosciences Inc. Treatment of tauopathies
SG10201912964PA (en) 2011-09-19 2020-02-27 Axon Neuroscience Se Protein-based therapy and diagnosis of tau-mediated pathology in alzheimer's disease
BR122021017560B1 (en) 2011-10-07 2023-03-07 Katholieke Universiteit Leuven ANTIBODY, POLYNUCLEOTIDE, PHARMACEUTICAL COMPOSITION, USES OF AN ANTIBODY, IN VITRO METHOD, POST-MORTEM DETECTION METHOD OF PHOSPHO-TAU MULTIMERS, IN VITRO METHOD OF DETECTION OF THE FORMATION OF AN IMMUNE COMPLEX, TEST KITS, ISOLATED CELL LINE AND METHOD OF IN VITRO DETECTION OF PHOSPHO-TAU MULTIMERS
SI2794654T1 (en) 2011-12-20 2019-08-30 Janssen Biotech, Inc. Anti-phf-tau antibodies and their uses
JP6293731B2 (en) * 2012-04-05 2018-03-14 エーシー イミューン エス．エー． Humanized tau antibody
KR102494798B1 (en) 2012-07-03 2023-02-06 워싱턴 유니버시티 Antibodies to tau
SI2885010T1 (en) 2012-08-16 2020-07-31 Ipierian, Inc. Methods of treating a tauopathy
US20140056901A1 (en) 2012-08-21 2014-02-27 The Institute For Molecular Medicine Anti-tau antibodies and compositions for and methods of making and using in treatment, diagnosis and monitoring of tauopathies
WO2014031697A2 (en) 2012-08-21 2014-02-27 The Institute Of Molecular Medicine COMPOSITIONS AND METHODS RELATED TO DISEASES ASSOCIATED WITH DEPOSITS OF AMYLOID, TAU, AND α-SYNUCLEIN
MX2015008024A (en) 2012-12-21 2016-08-08 Biogen Int Neuroscience Gmbh Human anti-tau antibodies.
US9259211B2 (en) 2012-12-24 2016-02-16 Transmed7, Llc Automated, selectable, soft tissue excision biopsy devices and methods
US8980270B2 (en) 2013-01-18 2015-03-17 Ipierian, Inc. Methods of treating a tauopathy
EA035943B1 (en) 2013-03-13 2020-09-03 Протена Биосайенсес Лимитед Antibody binding to human tau protein
CN105899230B (en) 2013-11-27 2020-06-09 伊皮埃里安股份有限公司 Methods of treating tauopathy
PL3083680T3 (en) 2013-12-20 2020-06-29 F. Hoffmann-La Roche Ag Humanized anti-tau(ps422) antibodies and methods of use
WO2015122922A1 (en) 2014-02-14 2015-08-20 Ipierian, Inc. Tau peptides, anti-tau antibodies, and methods of use thereof
TWI734975B (en) 2014-06-27 2021-08-01 美商Ｃ２Ｎ醫療診斷有限責任公司 Humanized anti-tau antibodies
CA3001724A1 (en) 2014-10-10 2016-04-14 National Research Council Of Canada Anti-tau antibody and uses thereof
US10323082B2 (en) 2014-10-14 2019-06-18 The Research Foundation For Mental Hygiene, Inc. Treatment of tauopathies by passive immunization targeting the N-terminal projection domain of tau
CA2874083C (en) 2014-12-05 2024-01-02 Universite Laval Tdp-43-binding polypeptides useful for the treatment of neurodegenerative diseases
EP3261670A4 (en) 2015-02-24 2018-08-01 Rpeptide, LLC Anti-tau antibodies
AR103713A1 (en) 2015-02-26 2017-05-31 Lilly Co Eli ANTIBODIES AGAINST TAU AND ITS USES
US10112990B2 (en) 2015-06-05 2018-10-30 Genentech, Inc. Anti-Tau antibodies and methods of use
EP3307320A4 (en) 2015-06-12 2019-03-06 C2N Diagnostics LLC Stable formulations of humanized anti-tau antibody
EP3319983A1 (en) 2015-07-06 2018-05-16 UCB Biopharma SPRL Tau-binding antibodies
MA42380A (en) 2015-07-06 2018-05-16 Ucb Biopharma Sprl ANTIBODIES BONDING TO TAU
JO3711B1 (en) 2015-07-13 2021-01-31 H Lundbeck As Antibodies specific for hyperphosphorylated tau and methods of use thereof
US20190224339A1 (en) 2016-04-29 2019-07-25 Voyager Therapeutics, Inc. Compositions for the treatment of disease
CA3022515A1 (en) 2016-05-02 2017-11-09 Prothena Biosciences Limited Antibodies recognizing tau
KR102551971B1 (en) 2016-07-12 2023-07-07 하. 룬드벡 아크티에셀스카브 Antibodies specific for hyperphosphorylated tau and methods for their use
KR20230146126A (en) 2016-12-07 2023-10-18 제넨테크, 인크. Anti-tau antibodies and methods of use
CN117820467A (en) 2016-12-07 2024-04-05 基因泰克公司 anti-TAU antibodies and methods of use
SG10201911225WA (en) 2017-03-28 2020-01-30 Genentech Inc Methods of treating neurodegenerative diseases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013007839A1 (en) * 2011-07-14 2013-01-17 Adx Neurosciences Nv Antibodies to phosphorylated tau aggregates
WO2014059442A2 (en) * 2012-10-12 2014-04-17 Arizona Board Agents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University Antibody based reagents that specifically recognize toxic oligomeric forms of tau
WO2014150877A2 (en) * 2013-03-15 2014-09-25 Ac Immune S.A. Anti-tau antibodies and methods of use
WO2014200921A1 (en) * 2013-06-10 2014-12-18 Ipierian, Inc. Methods of treating a tauopathy

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114174515A (en) * 2019-05-27 2022-03-11 英属哥伦比亚大学 Conformation-specific epitopes in tau, antibodies thereto and methods related thereto
CN113005096A (en) * 2021-01-19 2021-06-22 华中科技大学 Hybridoma cell strain secreting anti-serine phosphorylation tau protein monoclonal antibody

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